7-Amido-isoindolyl compounds and their pharmaceutical uses

ABSTRACT

The invention encompasses 7-amido-isoindolyl compounds and methods of using these compounds and compositions in mammals for treatment, prevention or management of various diseases and disorders. Examples inlcude, but are not limited to, cancer, inflammatory bowel disease and myelodysplastic syndrome.

This application claims the benefit of U.S. Provisional Application No.60/454,155, filed Mar. 12, 2003, which is incorporated herein in itsentirety by reference.

1. FIELD OF THE INVENTION

The invention encompasses novel 7-amido-substituted isoindolylcompounds, pharmaceutical compositions of these compounds, and methodsof using these compounds and compositions in mammals for the treatment,prevention and management of diseases mediated by PDE4 inhibition,associated with abnormal TNF-α levels and/or mediated by MMP inhibition.

2. BACKGROUND OF THE INVENTION

2.1. TNF-α

Tumor necrosis factor alpha (TNF-α) is a cytokine that is releasedprimarily by inflammation and mononuclear phagocytes in response toimmunostimulators. TNF-α is capable of enhancing most cellularprocesses, such as differentiation, recruitment, proliferation, andproteolytic degradation. At low levels, TNF-α confers protection againstinfective agents, tumors, and tissue damage. However, TNF-α also hasrole in many diseases. When administered to mammals such as humans,TNF-α causes or aggravates inflammation, fever, cardiovascular effects,hemorrhage, coagulation, and acute phase responses similar to those seenduring acute infections and shock states. Enhanced or unregulated TNF-αproduction has been implicated in a number of diseases and medicalconditions, for example, cancers, such as solid tumors and blood-borntumors; heart disease, such as congestive heart failure; and viral,genetic, inflammatory, allergic, and autoimmune diseases.

Cancer is a particularly devastating disease, and increases in bloodTNF-α levels are implicated in the risk of and the spreading of cancer.Normally, in healthy subjects, cancer cells fail to survive in thecirculatory system, one of the reasons being that the lining of bloodvessels acts as a barrier to tumor-cell extravasation. However,increased levels of cytokines have been shown to substantially increasethe adhesion of cancer cells to endothelium in vitro. One explanation isthat cytokines, such as TNF-α stimulate the biosynthesis and expressionof a cell surface receptors called ELAM-1 (endothelial leukocyteadhesion molecule). ELAM-1 is a member of a family of calcium-dependentcell adhesion receptors, known as LEC-CAMs, which includes LECAM-1 andGMP-140. During an inflammatory response, ELAM-1 on endothelial cellsfunctions as a “homing receptor” for leukocytes. ELAM-1 on endothelialcells was shown to mediate the increased adhesion of colon cancer cellsto endothelium treated with cytokines (Rice et al., 1989, Science246:1303–1306).

Inflammatory diseases such as arthritis, related arthritic conditions(e.g., osteoarthritis and rheumatoid arthritis), inflammatory boweldisease, sepsis, psoriasis, chronic obstructive pulmonary diseases andchronic inflammatory pulmonary diseases are also prevalent andproblematic ailments. TNF-α plays a central role in the inflammatoryresponse and the administration of their antagonists block chronic andacute responses in animal models of inflammatory disease.

Enhanced or unregulated TNF-α production has been implicated in viral,genetic, inflammatory, allergic, and autoimmune diseases. Examples ofsuch diseases include, but are not limited to: HIV; hepatitis; adultrespiratory distress syndrome; bone-resorption diseases; chronicobstructive pulmonary diseases; chronic pulmonary inflammatory diseases;dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock;hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury;meningitis; psoriasis; fibrotic disease; cachexia; graft versus hostdisease (GVHD); graft rejection; auto-immune disease; rheumatoidspondylitis; arthritic conditions, such as rheumatoid arthritis,rheumatoid spondylitis and osteoarthritis; osteoporosis;inflammatory-bowel disease; Crohn's disease; ulcerative colitis;multiple sclerosis; systemic lupus erythrematosus; ENL in leprosy;radiation damage; asthma; and hyperoxic alveolar injury. Tracey et al.,1987, Nature 330:662–664 and Hinshaw et al., 1990, Circ. Shock30:279–292 (endotoxic shock); Dezube et al., 1990, Lancet, 335:662(cachexia ); Millar et al., 1989, Lancet 2:712–714 and Ferrai-Balivieraet al., 1989, Arch. Surg. 124:1400–1405 (adult respiratory distresssyndrome); Bertolini et al., 1986, Nature 319:516–518, Johnson etal.,1989, Endocrinology 124:1424–1427, Holler et al., 1990, Blood75:1011–1016, and Grau et al., 1989, N. Engl. J. Med. 320:1586–1591(bone resorption diseases); Pignet et al., 1990, Nature, 344:245–247,Bissonnette et al., 1989, Inflammation 13:329–339 and Baughman et al.,1990, J. Lab. Clin. Med. 115:36–42 (chronic pulmonary inflammatorydiseases); Elliot et al., 1995, Int. J. Pharmac. 17:141–145 (rheumatoidarthritis); von Dullemen et al., 1995, Gastroenterology 109:129–135(Crohn's disease); Duh et al., 1989, Proc. Nat. Acad. Sci. 86:5974–5978,Poll et al., 1990, Proc. Nat. Acad. Sci. 87:782–785, Monto et al., 1990,Blood 79:2670, Clouse et al., 1989, J. Immunol. 142, 431–438, Poll etal., 1992, AIDS Res. Hum. Retrovirus, 191–197, Poli et al. 1990, Proc.Natl. Acad. Sci. 87:782–784, Folks et al., 1989, Proc. Natl. Acad. Sci.86:2365–2368 (HIV and opportunistic infections resulting from HIV).

2.2. PDE4

Adenosine 3′,5′-cyclic monophosphate (cAMP) also plays a role in manydiseases and conditions, such as, but not limited to asthma andinflammation (Lowe and Cheng, Drugs of the Future, 17(9), 799–807,1992). It has been shown that the elevation of cAMP in inflammatoryleukocytes inhibits their activation and the subsequent release ofinflammatory mediators, including TNF-α and nuclear factor κB (NF-κB).Increased levels of cAMP also lead to the relaxation of airway smoothmuscle.

It is believed that primary cellular mechanism for the inactivation ofcAMP is the breakdown of cAMP by a family of isoenzymes referred to ascyclic nucleotide phosphodiesterases (PDE) (Beavo and Reitsnyder, Trendsin Pharm., 11, 150–155, 1990). There are twelve known members of thefamily of PDEs. It is recognized that the inhibition of PDE type IV(PDE4) is particularly effective in both the inhibition of inflammatorymediated release and the relaxation of airway smooth muscle (Verghese,et al., Journal of Pharmacology and Experimental Therapeutics, 272(3),1313–1320, 1995). Thus, compounds that specifically inhibit PDE4 mayinhibit inflammation and aid the relaxation of airway smooth muscle witha minimum of unwanted side effects, such as cardiovascular oranti-platelet effects.

The PDE4 family that is specific for cAMP is currently the largest andis composed of at least 4 isozymes (a–d), and multiple splice variants(Houslay, M. D. et al. in Advances in Pharmacology 44, eds. J. August etal., p. 225, 1998). There may be over 20 PDE4 isoforms expressed in acell specific pattern regulated by a number of different promoters.Disease states for which selective PDE4 inhibitors have been soughtinclude: asthma, atopic dermatitis, depression, reperfusion injury,septic shock, toxic shock, endotoxic shock, adult respiratory distresssyndrome, autoimmune diabetes, diabetes insipidus, multi-infarctdementia, AIDS, cancer, Crohn's disease, multiple sclerosis, cerebralischemia, psoriasis, allograft rejection, restenosis, ulceratiavecolitis, cachexia, cerebral malaria, allergic rhino-conjunctivitis,osteoarthritis, rheumatoid arthrirtis, chronic obstructive pulmonarydisease (COPD), chronic bronchitis, cosinophilic granuloma, andautoimmune encephalomyelitis (Houslay et al., 1998). PDE4 is present inthe brain and major inflammatory cells and has been found in abnormallyelevated levels in a number of diseases including atopic dermatitis oreczema, asthma, and hay fever among others (reference OHSU flyer and J.of Allergy and Clinical Immunology, 70: 452–457, 1982 by Grewe et al.).In individuals suffering from atopic diseases elevated PDE-4 activity isfound in their peripheral blood mononuclear leukocytes, T cells, mastcells, neutrophils and basophils. This increased PDE activity decreasescAMP levels and results in a breakdown of cAMP control in these cells.This results in increased immune responses in the blood and tissues ofthose that are affected.

Some PDE 4 inhibitors reportedly have a broad spectrum ofanti-inflammatory activity, with impressive activity in models ofasthma, chronic obstructive pulmonary disorder (COPD) and other allergicdisorders such as atopic dermatitis and hay fever. PDE 4 inhibitors thathave been used include theophylline, rolipram, denbufylline, ARIFLO,ROFLUMILAST, CDP 840 (a tri-aryl ethane) and CP80633 (a pyrimidone).PDE4 inhibitors have been shown to influence eosinophil responses,decrease basophil histamine release, decrease IgE, PGE2, IL10 synthesis,and decrease anti-CD3 stimulated Il-4 production. Similarly, PDE4inhibitors have been shown to block neutrophil functions. Neutrophilsplay a major role in asthma, chronic obstructive pulmonary disorder(COPD) and other allergic disorders. PDE4 inhibitors have been shown toinhibit the release of adhesion molecules, reactive oxygen species,interleukin (IL)-8 and neutrophil elastase, associated with neutrophilswhich disrupt the architecture of the lung and therefore airwayfunction. PDE4 inhibitors influence multiple functional pathways, act onmultiple immune and inflammatory pathways, and influence synthesis orrelease of numerous immune mediators. J. M. Hanifin and S. C. Chan,“Atopic Dermatitis—Therapeutic Implication for New PhosphodiesteraseInhibitors,” Monocyte Dysregulation of T Cells in AACI News, Jul. 2,1995; J. M. Hanifin et al., “Type 4 Phosphodiesterase Inhibitors Haveclinical and In Vitro Anti-inflammatory Effects in Atopic Dermatitis,”Journal of Investigative Dermatology, 1996, 107, pp51–56).

Some of the first generation of PDE-4 inhibitors are effective ininhibiting PDE4 activity and alleviating a number of the inflammatoryproblems caused by over expression of this enzyme. However, theireffectiveness is limited by side effects, particularly when usedsystemically, such as nausea and vomiting. Huang et al., Curr. Opin. InChem. Biol. 2001, 5:432–438. Indeed, all of the PDE-4 inhibitorsdeveloped to date have been small molecule compounds with centralnervous system and gastrointestinal side effects, e.g., headache,nausea/emesis, and gastric secretion.

2.3. MMP

Matrix metalloproteinases (MMPs) are a family of proteases (enzymes)involved in the degradation and remodeling of connective tissues.Excessive degradation of extracellular matrix by MMPs is implicated inthe pathogenesis of many diseases, including rheumatoid arthritis,osteoarthritis, cancer, multiple sclerosis, bone resorptive diseases(such as osteoporosis), chronic obstructive pulmonary disease,restenosis, cerebral hemorrhaging associated with stroke, periodontaldisease, aberrant angiogenesis, tumor invasion and metastasis, cornealand gastric ulceration, ulceration of skin, aneurysmal disease, and incomplications of diabetes. MMP inhibition is, therefore, recognized as agood target for therapeutic intervention of this type of diseases. Manycompounds having MMP inhibition activities have been reported (R. A.Nigel et al, Current Opinion on Therapeutic Patents, Vol. 4, 7–16,(1994), R. P. Beckett et al, Drug Discovery Today, Vol. 1, 16–26,(1996)). However, most are peptide derivatives based on the amino acidsequence of the enzymatic cleavage site in the collagen moleculeconstituting the substrate of MMP. A need exists for small moleculeinhibitors of MMP.

3. SUMMARY OF THE INVENTION

The present invention provides compounds which are useful in thetreatment of diseases mediated by the inhibition of PDE4, TNF-α and/orMMP, and other various diseases or disorders. The invention alsoprovides pharmaceutical compositions comprising these compounds andmethods of using the subject compounds and compositions for thetreatment of a variety of diseases.

One embodiment of the invention encompasses compounds of formula (I):

wherein:

-   Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—;-   X is H;-   Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,    (C₁₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl),    (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)-NH₂,    (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH),    (C₀₋₄-alkyl)-dichloropyridine, or CH₂NSO₂—(C₁₋₄-alkyl);-   R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or    (C₁₋₄-alkyl)-cycloalkyl;-   R³ is, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);-   R⁴ is H;-   R⁵ is —OH, or —O—C(O)R⁶;-   R⁶ is C₁₋₈-alkyl, amino-(C₁₋₈-alkyl),    (C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl), C₃₋₆-cycloalkyl, phenyl, benzyl, or    aryl;    and pharmaceutically acceptable salts, solvates, hydrates,    stereoisomers, clathrates, or prodrugs thereof.

In one embodiment, Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl,(C₀₋₄-alkyl)-OH, (C₁₋₄-alkyl)-O—(C₁₋₄-alkyl),(C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl),(C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), orCH₂NSO₂—(C₁₋₄-alkyl).

This invention also encompasses compounds of formula (II):

wherein:

-   Y is —C(O)—, —CH₂—, —CH₂C(O)—, or —SO₂—;-   X is halogen, CN, NR₇R₈, NO₂, CH₃, or CF₃;-   Z is (C₀₋₄-alkyl)-SO₂(C₁₋₄-alkyl), (C₀₋₄-alkyl)-CN,    (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,    (C₀₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl),    (C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂,    (C₀₋₄-alkyl)-N(H)(OH), (C₀₋₄-alkyl)-dichloropyridine, or    (C₀₋₄-alkyl)-NSO₂(C₁₋₄-alkyl);-   W is C₃₋₆-cycloalkyl, (C₁₋₈-alkyl)-(C₃₋₆cycloalkyl),    (C₀₋₈-alkyl)-(C₃₋₆cycloalkyl)-NR₇R₈, (C₀₋₈-alkyl)-NR₇R₈,    (C₀₋₄alkyl)-CHR₉—(C₀₋₄alkyl)-NR₇R₈,-   R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or    (C₁₋₄-alkyl)-cycloalkyl;-   R³ is C₁₋₈-alkyl, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);-   R⁴ and R⁵ are independently H, C₁₋₈-alkyl,    (C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), OH, or OC(O)R⁶;-   R⁶ is C₁₋₈-alkyl, (C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl),    amino-(C₁₋₈-alkyl), phenyl, benzyl, or aryl;-   R₇ and R₈ are each independently H, C₁₋₈-alkyl,    (C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), phenyl, benzyl, aryl, or can be    taken together with the atom connecting them to form a 3 to 7    membered heterocycloalkyl or heteroaryl ring;-   R₉ is C₁₋₄ alkyl, (C₀₋₄-alkyl)-aryl, (C₀₋₄-alkyl)-(C₃₋₆-cycloalkyl),    (C₀₋₄alkyl)-heterocycle;    and pharmaceutically acceptable salts, solvates, hydrates,    stereoisomers, clathrates, or prodrugs thereof.

In another embodiment, Z is (C₀₋₄-alkyl)-SO₂(C₁₋₄-alkyl),(C₀₋₄-alkyl)-CN, (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,(C₀₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl),(C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), or(C₀₋₄-alkyl)-NSO₂(C₁₋₄-alkyl).

In another embodiment, W is:

In another embodiment, W is not

In another embodiment, this invention encompasses compounds of formula(III):

wherein:

-   R₁, R₂ and R₃ are independently H or C₁₋₈-alkyl, with the proviso    that at least one of R₁, R₂ and R₃ is not H;    and pharmaceutically acceptable salts, solvates, hydrates,    stereoisomers, clathrates, or prodrugs thereof.

In one embodiment, with regard to formula III, R₁ is H and R₂ and R₃ areboth methyl.

In another embodiment, with regard to formula III, R₁, R₂ and R₃ aremethyl.

In another embodiment, the invention encompasses a method of modulating(e.g., inhibiting) the production or lowering the levels of PDE4 in amammal or a mammalian cell comprising administering to said mammal aneffective amount of a compound of the invention (e.g., compounds offormula I, II or III).

Another embodiment of the invention encompasses a method of modulatingthe production of, or lowering the levels of, TNF-α in a mammal or amammalian cell comprising administering to said mammal or mammalian cellan effective amount of a compound of the invention.

In yet another embodiment, the invention encompasses a method ofmodulating the production of, or inhibiting or lowering the levels of,MMP in a mammal or a mammalian cell comprising administering to saidmammal or mammalian cell an effective amount of a compound of theinvention.

Other embodiments of the invention encompass methods of treating,preventing and managing various disease or disorders, such as, but notlimited to: central nervous system (CNS) disorders; myelodysplasticsyndrome (MDS) and related syndromes; complex regional pain syndrome(CRPS) and related syndromes; cancer and related diseases; maculardegeneration (MD) and related syndromes; myeloproliferative diseases(MPD) and related syndromes; and asbestos-related diseases anddisorders.

Pharmaceutical compositions, modes of administration, formulations, andmethods of using the above compounds alone or in combination aredescribed in more detail below.

3.1. Abbreviations and Definitions

The abbreviations used herein are conventional, unless otherwisedefined.

The terms “treat,” “treating” and “treatment,” as used herein,contemplate an action that occurs while a patient is suffering from thespecified disease or disorder, which reduces the severity of the diseaseor disorder.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before apatient begins to suffer from the specified disease or disorder, whichinhibits or reduces the severity of the disease or disorder.

As used herein, and unless otherwise indicated, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease or disorder in a patient who has already suffered fromthe disease or disorder, and/or lengthening the time that a patient whohas suffered from the disease or disorder remains in remission. Theterms encompass modulating the threshold, development and/or duration ofthe disease or disorder, or changing the way that a patient responds tothe disease or disorder.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated as well as to alleviate or eradicate the cause ofthe disease itself.

As used herein, the term “PDE4-responsive condition or disorder” or“mediated by PDE4 inhibition” or “mediated by inhibition of PDE4” refersto a condition or disorder that responds favorably to modulation of PDE4activity. Favorable responses to PDE4 modulation include alleviation orabrogation of the disease and/or its attendant symptoms, inhibition ofthe disease, i.e., arrest or reduction of the development of thedisease, or its clinical symptoms, and regression of the disease or itsclinical symptoms. A PDE4-responsive condition or disease may becompletely or partially responsive to PDE4 modulation. A PDE4-responsivecondition or disorder may be associated with inappropriate, e.g., lessthan or greater than normal, PDE4-activity. Inappropriate PDE4functional activity might arise as the result of PDE4 expression incells which normally do not express PDE4, decreased PDE4 expression(leading to, e.g., lipid and metabolic disorders and diseases) orincreased PDE4 expression. A PDE4-responsive condition or diseaseincludes a PDE4-mediated condition or disease.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, acyclic or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multi-valentradicals, having the number of carbon atoms designated (e.g., C₀₋₁₀means one to ten carbons, or not present, i.e., C₀ means the moiety doesnot exist). Examples of saturated hydrocarbon radicals include groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologsand isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, andthe like. An unsaturated alkyl group is one having one or more doublebonds or triple bonds. Examples of unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “alkyl,” unlessotherwise noted, is also meant to include those derivatives of alkyldefined in more detail below as “heteroalkyl,” “cycloalkyl” and“alkylene.” The term “alkylene” by itself or as part of anothersubstituent means a divalent radical derived from an alkane, asexemplified by —CH₂CH₂CH₂CH₂—. Typically, an alkyl group will have from1 to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain,acyclic or cyclic hydrocarbon radical, or combinations thereof,consisting of the stated number of carbon atoms and from one to threeheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N and S may be placed at any interior position of the heteroalkyl group.The heteroatom Si may be placed at any position of the heteroalkylgroup, including the position at which the alkyl group is attached tothe remainder of the molecule. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Also included in the term“heteroalkyl” are those radicals described in more detail below as“heteroalkylene” and “heterocycloalkyl.” The term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini. For alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Thus, the terms“cycloalkyl” and “heterocycloalkyl” are meant to be included in theterms “alkyl” and “heteroalkyl,” respectively. Furthermore, the term“C₃₋₁₈ cycloalkyl,” means a cycloalkyl with 3 to 18 carbon atoms.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl),1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include alkyl substituted with halogen atoms which can be thesame or different, in a number ranging from one to (2m′+1), where m′ isthe total number of carbon atoms in the alkyl group. For example, theterm “halo(C₁–C₄)alkyl” includes trifluoromethyl, 2,2,2-trifluoroethyl,4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term “haloalkyl”includes monohaloalkyl (alkyl substituted with one halogen atom) andpolyhaloalkyl (alkyl substituted with halogen atoms in a number rangingfrom two to (2m′+1) halogen atoms, where m′ is the total number ofcarbon atoms in the alkyl group). The term “perhaloalkyl” means, unlessotherwise stated, alkyl substituted with (2m′+1) halogen atoms, where m′is the total number of carbon atoms in the alkyl group. For example, theterm “perhalo(C₁–C₄)alkyl” includes trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

The term “aryl,” employed alone or in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwise stated,an aromatic substituent which can be a single ring or multiple rings (upto three rings) which are fused together or linked covalently. The ringsmay each contain from zero to four heteroatoms selected from N, O, andS, wherein the nitrogen and sulfur atoms are optionally oxidized, andthe nitrogen atom(s) are optionally quaternized. The aryl groups thatcontain heteroatoms may be referred to as “heteroaryl” and can beattached to the remainder of the molecule through a heteroatom.Non-limiting examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, oxadiazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, triazolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl,5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of theabove noted aryl ring systems are selected from the group of acceptablesubstituents described below.

The term “arylalkyl” includes those radicals in which an aryl group isattached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl andthe like) or a heteroalkyl group (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl” and “aryl”)includes both substituted and unsubstituted forms of the indicatedradical. Preferred substituents for each type of radical are providedbelow.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R,″ —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2N+1), whereN is the total number of carbon atoms in such radical, and where R′, R″and R′″ each independently refer to hydrogen, unsubstituted(C₁–C₈)alkyland heteroalkyl, unsubstituted aryl, aryl substituted with 1–3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C₁–C₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the carbon atoms to which they are attached with thenitrogen atom to form a 5-, 6- or 7-membered ring containing from 1 to 3heteroatoms selected from the group consisting of N, O and S. Forexample, —NR′R″ includes 1-pyrrolidinyl and 4-morpholinyl. From theabove discussion of substituents, one of skill in the art willunderstand that the term “alkyl” includes substituted alkyl groupsincluding haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃,—C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similarly, substituents for the aryl groups are varied and can beselected from: -halogen, —OR′, —OC(O)R′, —NR′R,″ —SR′, —R′, —CN, —NO₂,—CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, fluoro(C₁–C₄)alkoxy, andfluoro(C₁–C₄)alkyl, in a number ranging from zero to the total number ofopen valences on the aromatic ring system; and where each R′, R″ and R′″is independently selected from hydrogen, (C₁–C₈)alkyl and heteroalkyl,unsubstituted aryl, (unsubstituted aryl)-(C₁–C₄)alkyl and (unsubstitutedaryl)oxy-(C₁–C₄)alkyl.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N)and sulfur (S). In certain embodiments, the term further encompassessilicon (Si).

The term “pharmaceutically acceptable salt” includes salts which areprepared with relatively nontoxic acids or bases, depending on theparticular substituents found on the compounds described herein. Whencompounds of the present invention contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, and magnesium salts. Whencompounds of the present invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, nitric,carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, andphosphorous acids, as well as the salts derived from relatively nontoxicorganic acids such as acetic, propionic, isobutyric, oxalic, maleic,malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic,benzenesulfonic, p-tolylsulfonic, citric, tartaric, and methanesulfonicacids. Also included are salts of amino acids, such as arginate, andsalts of organic acids, such as glucuronic and galactunoric acids. See,e.g., Berge et al. (1977) J. Pharm. Sci. 66:1–19. Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Neutral forms of some compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of a compound can differ from itsvarious salt forms in certain physical properties, such as solubility inpolar solvents, but the salts are typically equivalent to the parentform of the compound for the purposes of the present invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general,solvated forms are equivalent to unsolvated forms. Certain compounds ofthe invention may exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the uses contemplated bythe present invention, and are encompassed by the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or stereo-centers) or double bonds; the racemates,enantiomers, diastereomers, geometric isomers and mixtures thereof areall intended to be encompassed by this invention.

Compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds are useful astherapeutic agents, e.g., cancer therapeutic agents, research reagents,e.g., assay reagents, and diagnostic agents, e.g., in vivo imagingagents. All isotopic variations of the compounds of the presentinvention, whether radioactive or not, are intended to be encompassedwithin the scope of the present invention.

4. DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses novel compounds and compositions that can beused to treat, prevent or manage diseases and disorders in mammals(e.g., humans). Examples of such diseases or disorders include, but arenot limited to: cancer; viral, genetic, inflammatory, allergic, andautoitmnune diseases; bacterial infections; CNS disorders; MDS andrelated syndromes; CRPS and related syndromes; MD and related syndromes;MPD and related syndromes; and asbestos-related diseases or disorders.Compounds of the invention can be used to treat, prevent or managediseases caused or aggravated by excessive, insufficient or unregulatedlevels of PDE4, TNF-α, and/or MMP.

One embodiment of the invention encompasses compounds of formula (I):

wherein:

-   Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—;-   X is H;-   Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,    (C₁₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl),    (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)-NH₂,    (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)2, (C₀₋₄-alkyl)-N(H)(OH),    (C₀₋₄-alkyl)-dichloropyridine, or CH₂NSO₂-(C₁₋₄-alkyl);-   R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or    (C₁₋₄-alkyl)-cycloalkyl;-   R³ is, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);-   R⁴ is H;-   R⁵ is —OH, or —O—C(O)R⁶;-   R⁶ is C₁₋₈-alkyl, amino-(C₁₋₈-alkyl),    (C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl), C₃₋₆-cycloalkyl, phenyl, benzyl, or    aryl;    and pharmaceutically acceptable salts, solvates, hydrates,    stereoisomers, clathrates, or prodrugs thereof.

In one embodiment, Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl,(C₀₋₄-alkyl)-OH, (C₁₋₄-alkyl)-O—(C₁₋₄-alkyl),(C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl),(C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), orCH₂NSO₂—(C₁₋₄-alkyl).

This invention also encompasses compounds of formula (II):

wherein:

-   Y is —C(O)—, —CH₂—, —CH₂C(O)—, or —SO₂—;-   X is halogen, CN, NR₇R₈, NO₂, CH₃, or CF₃;-   Z is (C₀₋₄-alkyl)-SO₂(C₁₋₄-alkyl), (C₀₋₄-alkyl)-CN,    (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,    (C₀₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl),    (C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂,    (C₀₋₄-alkyl)-N(H)(OH), (C₀₋₄-alkyl)-dichloropyridine, or    (C₀₋₄-alkyl)-NSO₂(C₁₋₄-alkyl);-   W is C₃₋₆-cycloalkyl, (C₁₋₈-alkyl)-(C₃₋₆cycloalkyl),    (C₀₋₈-alkyl)-(C₃₋₆cycloalkyl)-NR₇R₈, (C₀₋₈-alkyl)-NR₇R₈,    (C₀₋₄alkyl)-CHR₉—(C₀₋₄alkyl)-NR₇R₈,-   R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or    (C₁₋₄-alkyl)-cycloalkyl;-   R³ is C₁₋₈-alkyl, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);-   R⁴ and R⁵ are independently H, C₁₋₈-alkyl,    (C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), OH, or OC(O)R⁶;-   R⁶ is C₁₋₈-alkyl, (C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl),    amino-(C₁₋₈-alkyl), phenyl, benzyl, or aryl;-   R₇ and R₈ are each independently H, C₁₋₈-alkyl,    (C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), phenyl, benzyl, aryl, or can be    taken together with the atom connecting them to form a 3 to 7    membered heterocycloalkyl or heteroaryl ring;-   R₉ is C₁₋₄ alkyl, (C₀₋₄-alkyl)-aryl, (C₀₋₄-alkyl)-(C₃₋₆-cycloalkyl),    (C₀₋₄alkyl)-heterocycle;    and pharmaceutically acceptable salts, solvates, hydrates,    stereoisomers, clathrates, or prodrugs thereof.

In another embodiment, Z is (C₀₋₄-alkyl)-SO₂(C₁₋₄-alkyl),(C₀₋₄-alkyl)-CN, (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,(C₀₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl),(C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), or(C₀₋₄-alkyl)-NSO₂(C1–4-alkyl).

In another embodiment, W is:

In another embodiment, W is not

In another embodiment, this invention encompasses compounds of formula(III):

wherein:

-   R₁, R₂ and R₃ are independently H or C₁₋₈-alkyl, with the proviso    that at least one of R₁, R₂ and R₃ is not H;    and pharmaceutically acceptable salts, solvates, hydrates,    stereoisomers, clathrates, or prodrugs thereof.

In one embodiment, with regard to formula III, R₁ is H and R₂ and R₃ areboth methyl.

In another embodiment, with regard to formula III, R₁, R₂ and R₃ aremethyl.

Examples of compounds of the invention include, but are not limited to,those listed in Table I below:

TABLE I No. Compound Name 1

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide2

(3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate 3

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide4

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide5

(1R)-Cyclopropanecarboxylicacid{2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide6

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-ureido-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide7

(1R)-Cyclopropanecarboxylicacid{2-[3-dimethylamino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amidehydrochloride8

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide9

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide10

(1R)-Cyclopropanecarboxylicacid{2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide11

(3R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfinyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide12

(3R)-3-[4-Chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid 13

(3R)-3-[4-Chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid methyl ester 14

(1R)-Cyclopropanecarboxylicacid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide15

(1R)-Cyclopropanecarboxylicacid{7-chloro-2-[2-dimethylcarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide16

(1R)-Cyclopropanecarboxylicacid{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide17

(1R)-Cyclopropanecarboxylicacid{2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide18

(1S)-Cyclopropanecarboxylicacid{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide19

(1S)-Cyclopropanecarboxylicacid{7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide20

Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide21

Cyclopropanecarboxylic acid{7-chloro-2-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide22

Cyclopropanecarboxylic acid{2-[2-(3,5-dichloro-pyridin-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide23

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide24

(1R)-Cyclopropanecarboxylicacid{2-[2-cyclopropanecarbonyloxycar-bamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide25

(1R)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-isobutyryloxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol4-yl}-amide26

(1R)-Cyclopropanecarboxylicacid{2-[2-(2,2-dimethyl-propionyloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide27

(1R)-Cyclopropanecarboxylicacid{2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide28

(1S)-Cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide29

(1S)-3-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea30

(1S)-N-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo2,3-dihydro-1H-isoindol-4-yl}-2-(4-methyl-piperazin-1-yl)-acetamide31

(1S)-N-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-morpholin-4-yl-acetamide;hydrochloride32

(1S)-N-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-dimethylamino-acetamide;hydrochloride33

N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2,2-dimethyl-propionamide34

N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide

Compounds of the invention generally exist in solid form and can berecrystallized according to well-known methods affording high-puritycrystals, preferably, in greater than 95% purity, more preferably, ingreater than 98% purity. A narrow melting-point range is often anindication of purity. Thus, preferred compounds of the invention have amelting point within a range of 3° C. to 4° C., more preferably, withina range of 2° C.

Various compounds of the invention contain one or more chiral centers,and can exist as racemic mixtures of enantiomers or mixtures ofdiastereomers. This invention encompasses the use of stereomericallypure forms of such compounds, as well as the use of mixtures of thoseforms. For example, mixtures comprising equal or unequal amounts of theenantiomers of a particular compounds of the invention may be used inmethods and compositions of the invention. These isomers may beasymmetrically synthesized or resolved using standard techniques such aschiral columns or chiral resolving agents. See, e.g., Jacques, J., etal., Enantiomers, Racemates and Resolutions (Wiley-Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); andWilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

Compounds of the invention can contain one or more chiral centers and/ordouble bonds and, therefore, exist as stereoisomers and geometircisomers. Chemical structures and portions of chemical structuresdepicted herein that do not indicate stereochemistry encompass all oftheir enantiomers and stereoisomers, e.g., both the stereomerically pureforms stereoisomeric mixtures.

As used herein, and unless otherwise indicated, the term “stereoisomericmixture” encompasses racemic mixtures as well as enatiomericallyenriched mixtures (e.g., R/S=30/70, 35/65, 40/60, 45/55, 55/45, 60/40,65/35 and 70/30).

As used herein, and unless otherwise indicated, the term“stereomerically pure” or “enantiomerically pure” means that a compoundone stereoisomer and is substantially free of its counter stereoisomeror enantiomer. For example, a compound is stereomerically oreneantiomerically pure when the compound contains 80%, 90%, or 95% ormore of one stereoisomer and 20%, 10%, or 5% or less of the counterstereoisomer. In certain cases, a compound of the invention isconsidered optically active or stereomerically/enantiomerically pure(i.e., substantially the R-form or substantially the S-form) withrespect to a chiral center when the compound is about 80% ee(enantiomeric excess) or greater, preferably, equal to or greater than90% ee with respect to a particular chiral center, and more preferably95% ee with respect to a particular chiral center. Thus, the inventionencompasses all enantiomerically pure, enantiomerically enriched, andracemic mixtures of compounds of Formula I, II, or III.

In one embodiment, the invention encompasses an enantiomerically Risomer of a compound of formula I, II or III, substantially free of itsS isomer, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof.

In another embodiment, the invention also encompasses anenantiomerically S isomer of a compound of formula I, II or III,substantially free of its R isomer, or a pharmaceutically acceptablesalt, solvate, hydrate, clathrate, or prodrug thereof.

Enantiomeric and stereoisomeric mixtures of compounds of the inventioncan be resolved into their component enantiomers or stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Enantiomers and stereoisomers can also be obtained fromstereomerically or enantiomerically pure intermediates, reagents, andcatalysts by well-known asymmetric synthetic methods.

The invention further encompasses prodrugs of compounds encompassed byFormulae I, II and III. As used herein, and unless otherwise indicated,the term “prodrug” means a derivative of a compound that can hydrolyze,oxidize, or otherwise react under biological conditions (in vitro or invivo) to provide the compound. Examples of prodrugs include, but are notlimited to, derivatives of compounds of the invention that comprisebiohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Otherexamples of prodrugs include derivatives of compounds of the inventionthat comprise —NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typicallybe prepared using well-known methods, such as those described inBurger's Medicinal Chemistry and Drug Discovery, 172–178, 949–982(Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H.Bundgaard ed., Elselvier, New York 1985).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzablecarbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,”“biohydrolyzable phosphate” mean an amide, ester, carbamate, carbonate,ureide, or phosphate, respectively, of a compound that either: 1) doesnot interfere with the biological activity of the compound but canconfer upon that compound advantageous properties in vivo, such asuptake, duration of action, or onset of action; or 2) is biologicallyinactive but is converted in vivo to the biologically active compound.Examples of biohydrolyzable esters include, but are not limited to,lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl,acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, andpivaloyloxyethyl esters), lactonyl esters (such as phthalidyl andthiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such asmethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl andisopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters,and acylamino alkyl esters (such as acetamidomethyl esters). Examples ofbiohydrolyzable amides include, but are not limited to, lower alkylamides, -amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamatesinclude, but are not limited to, lower alkylamines, substitutedethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, and polyether amines.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure is to beaccorded more weight.

This invention provides pharmaceutical compositions comprising atherapeutically effective or a prophylactically effective amount of oneor more compounds of the invention and a pharmaceutically acceptablevehicle or carrier. A pharmaceutically acceptable vehicle or carrier cancomprise an excipient, diluent, or a mixture thereof. The term“therapeutically effective amount” means the amount of a compound of theinvention that will elicit the biological or medical response in amammal that is being that is being treated by the veterinarian orclinician. The term “prophylactically effective” means the amount of acompound of the invention that will prevent or inhibit affliction ormitigate affliction of a mammal with a medical condition that aveterinarian or clinician is trying to prevent, inhibit, or mitigate.

In another embodiment, the invention encompasses a method inhibitingPDE4 in a mammal comprising administering to said mammal an effectiveamount of a compound of the invention.

In another embodiment, the invention encompasses a method of modulatingthe production or lowering the levels of TNF-α in a mammal comprisingadministering to said mammal an effective amount of a compound of theinvention.

In yet another embodiment, the invention encompasses a method ofinhibiting MMP in a mammal comprising administering to said mammal aneffective amount of a compound of the invention.

In yet another embodiment, the invention encompasses a method oftreating undesired angiogenesis in a mammal comprising administering tosaid mammal an effective amount of a compound of the invention. Diseasesassociated with angiogenesis are well known in the art.

A separate embodiment of the invention encompasses methods of treating,preventing and managing Myelodysplastic Syndrome (MDS) which comprisesadministering to a patient in need of such treatment, prevention ormanagement a therapeutically or prophylactically effective amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. MDSrefers to a diverse group of hematopoietic stem cell disorders. MDS ischaracterized by a cellular marrow with impaired morphology andmaturation (dysmyelopoiesis), peripheral blood cytopenias, and avariable risk of progression to acute leukemia, resulting fromineffective blood cell production. The Merck Manual 953 (17th ed. 1999)and List et al., 1990, J. Clin. Oncol. 8:1424.

Another separate embodiment of the invention encompasses methods oftreating, preventing and managing Macular Degeneration (MD), whichcomprises administering to a patient in need of such treatment,prevention or management a therapeutically or prophylactically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. MDrefers to an eye disease that destroys central vision by damaging themacula.

A separate embodiment of the invention encompasses methods of treating,preventing and managing Myeloproliferative Disease (MPD) which comprisesadministering to a patient in need of such treatment, prevention ormanagement a therapeutically or prophylactically effective amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. MPDrefers to a group of disorders characterized by clonal abnormalities ofthe hematopoietic stem cell. See e.g., Current Medical Diagnosis &Treatment, pp. 499 (37th ed., Tierney et al. ed, Appleton & Lange,1998).

The invention also encompasses, a method of treating, preventing andmanaging Complex Regional Pain Syndrome (CRPS), which comprisesadministering to a patient in need of such treatment, prevention ormanagement a therapeutically or prophylactically effective amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before,during or after surgery or physical therapy directed at reducing oravoiding a symptom of complex regional pain syndrome in the patient.

In another embodiment, this invention encompasses a method of treating,preventing and managing a Central Nervous System (CNS) disorder, whichcomprises administering to a patient in need of such treatment,prevention or management a therapeutically or prophylactically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In another embodiment, this invention encompasses a method of treating,preventing or managing an asbestos-related disease or disorder, whichcomprises administering to a patient in need of such treatment,prevention or management a therapeutically or prophylactically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.Asbestos-related disease or disorder refers to a disease or disordercaused by an exposure to asbestos.

In still another embodiment, the invention encompasses methods oftreating, preventing and managing cancer in a mammal, comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention. The compounds of the invention can be used totreat, prevent or manage any cancer, for example, solid tumors andblood-born tumors. Specific examples of cancers treatable, preventableor manageable by compounds of the invention include, but are not limitedto: cancers of the skin, such as melanoma; lymph node; breast; cervix;uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum;mouth; brain; head and neck; throat; testes; kidney; pancreas; bone;spleen; liver; bladder; larynx; nasal passages; and AIDS-relatedcancers. The compounds are particularly useful for treating, preventingor managing cancers of the blood and bone marrow, such as multiplemyeloma and acute and chronic leukemias, for example, lymphoblastic,myelogenous, lymphocytic, and myelocytic leukemias. The compounds of theinvention can be used for treating, preventing or managing eitherprimary or metastatic tumors.

In yet one more embodiment, the invention encompasses methods oftreating, preventing and managing cancer in a mammal, comprisingadministering to a mammal in need thereof, a therapeutically effectiveamount of a compound of the invention and another therapeutic agent.

In yet another embodiment, the invention encompasses methods oftreating, preventing and managing inflammatory disorders in a mammal,comprising administering to said mammal a therapeutically effectiveamount of a compound of the invention. The compounds of the inventionare especially effective to treat, prevent or manage inflammatorydiseases related to the up-regulation of TNF-α including, but notlimited to, arthritic conditions, such as, rheumatoid arthritis, andosteoarthritis; rheumatoid spondylitis; psoriasis; post ischemicperfusion injury; inflammatory bowel disease; and chronic inflammatorypulmonary disease.

In one more embodiment still, the invention encompasses methods oftreating, preventing and managing inflammatory disorders in a mammal,comprising administering to a mammal in need thereof, a therapeuticallyeffective amount of a compound of the invention and anotheranti-inflammatory agent.

In a further embodiment, the invention encompasses methods of treating,preventing and managing heart disease in a mammal comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention. For example, the compounds of the inventioncan be used to treat, prevent or manage congestive heart failure,cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acuteviral myocarditis, cardiac allograft rejection, and myocardialinfarction.

In an additional embodiment, the invention encompasses methods oftreating, preventing and managing osteoporosis in a mammal comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention.

In a further embodiment, the invention encompasses methods of treating,preventing and managing viral, genetic, allergic, and autoimmunediseases. For example, the compounds are useful to treat, prevent ormanage diseases including, but not limited to, HIV, hepatitis, adultrespiratory distress syndrome, bone resorption diseases, chronicpulmonary inflammatory diseases, dermatitis, cystic fibrosis, septicshock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, postischemic reperfusion injury, meningitis, psoriasis, fibrotic disease,cachexia, graft versus host disease, graft rejection, auto-immunedisease, rheumatoid spondylitis, Crohn's disease, ulcerative colitis,inflammatory-bowel disease, multiple sclerosis, systemic lupuserythrematosus, ENL in leprosy, radiation damage, cancer, asthma, orhyperoxic alveolar injury in a mammal comprising administering to saidmammal a therapeutically effective amount of a compound of theinvention.

In still another embodiment, the invention encompasses methods oftreating, preventing and managing malaria, mycobacterial infection, oran opportunistic infection resulting from HIV in a mammal, comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention.

In still one more embodiment, the invention relates to treating,preventing or managing mammals having more than one of the conditionstreatable by a compound of the invention.

In the above embodiments, it is preferable that the mammal be in need ofthe treatment, prevention or management, that is, the mammal is actuallysuffering from a medical condition or at risk of a medical condition forwhich a compound of the invention can provide treatment, prevention ormanagement. However, the compounds of the invention can also beadministered to test animals that do not necessarily require suchtreatment, prevention or management.

In a further embodiment, the invention encompasses a method ofmodulating the production, preferably inhibiting, or lowering the levelsof PDE4 in a mammalian cell or tissue comprising contacting an effectiveamount of a compound of the invention with said mammalian cell ortissue.

In a further embodiment, the invention encompasses a method ofmodulating the production or lowering the levels of TNF-α in a mammaliancell or tissue comprising contacting an effective amount of a compoundof the invention with said mammalian cell or tissue.

In yet another embodiment, the invention encompasses a method ofmodulating the production or lowering the levels of MMP in a mammaliancell or tissue comprising contacting an effective amount of a compoundof the invention with said mammalian cell or tissue.

In these embodiments, the term “effective amount” means the amount ofthe compound that will induce the biological response sought by theresearcher, veterinarian, physician, or clinician. It should beunderstood that the cell can be in a cell culture or a tissue culture(in vitro) or in an organism (in vivo) including a human.

The present invention may be understood by reference to the detaileddescription and examples that are intended to exemplify non-limitingembodiments of the invention.

4.1. Preparation of the Compounds

The compounds can be prepared using methods which are known in generalfor the preparation of imides and 2,3-dihydro-1H-isoindolinones.However, the present invention also pertains to an improvement in theformation of the final compounds, as discussed below in greater detail.

An N-alkoxycarbonylimide and an amine thus are allowed to react in thepresence of a base such as sodium carbonate or sodium bicarbonatesubstantially as described by Shealy et al., Chem. & Ind., (1965)1030–1031) and Shealy et al., J. Pharm. Sci. 57, 757–764 (1968) to yieldthe N-substituted imide. Alternatively, a cyclic acid anhydride can bereacted with an appropriate amine to form an imide. Formation of acyclic imide also can be accomplished by refluxing a solution of anappropriately substituted dicarboxylic acid monoamide in anhydroustetrahydrofuran with N,N′-carbonyldiimidazole. Also, a2-bromomethyl-benzoic ester can be reacted with an appropriate amine toform a 2,3-dihydro-1H-isoindolinone as shown below.

Other methods of formation are described in U.S. Pat. No. 5,605,914 andInternational Publication No. WO 01/34606 A1 which are incorporatedherein in there entireties by reference.

4.2. Pharmaceutical Compositions

This invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier, excipient or diluent and one ormore compounds of the present invention.

One embodiment provides the subject compounds combined with apharmaceutically acceptable excipient such as sterile saline,methylcellulose solutions, detergent solutions or other medium, water,gelatin, oils, etc. The compounds or compositions may be administeredalone or in combination with any convenient carrier, diluent, etc., andsuch administration may be provided in single or multiple dosages. Thecompositions are sterile, particularly when used for parenteraldelivery. However, oral unit dosage forms need not be sterile. Usefulcarriers include water soluble and water insoluble solids, fatty acids,micelles, inverse micelles, liposomes and semi-solid or liquid media,including aqueous solutions and non-toxic organic solvents. All of theabove formulations may be treated with ultrasounds, stirred, mixed,high-shear mixed, heated, ground, milled, aerosolized, pulverized,lyophilized, etc., to form pharmaceutically acceptable compositions.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

The pharmaceutical compositions and methods of the present invention mayfurther comprise other therapeutically active compounds, as notedherein, useful in the treatment of metabolic disorders, cardiovasculardiseases, inflammatory conditions or neoplastic diseases and pathologiesassociated therewith (e.g., diabetic neuropathy) or other adjuvant. Inmany instances, compositions which include a compound of the inventionand an alternative agent have additive or synergistic effects whenadministered.

4.3. Methods of Treatment, Prevention and Management

In accordance with the invention, a compound or composition of theinvention is administered to a mammal, preferably, a human, with or atrisk of a disease or medical condition, for example, cancer, such assolid tumors and blood-born tumors. Specific examples of cancerstreatable, preventable or manageable by administering compounds of theinvention include, but are not limited to, disease of skin tissues,organs, blood, and vessels, including, but not limited to, cancers ofthe bladder, bone or blood, brain, breast, cervix, chest, colon,endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung,mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis,throat, and uterus. Specific cancers include, but are not limited to,advanced malignancy, amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastase, glioblastoma multiforms,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant glioma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma,karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuselarge B-Cell lymphoma, low grade follicular lymphoma, metastaticmelanoma (localized melanoma, including, but not limited to, ocularmelanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation; in particular,refractory to thalidomide.

The compounds of the invention are also useful to treat, prevent ormanage heart disease, such as congestive heart failure, cardiomyopathy,pulmonary edema, endotoxin-mediated septic shock, acute viralmyocarditis, cardiac allograft rejection, and myocardial infarction.

The compounds of the invention can also be used to treat, prevent ormanage viral, genetic, inflammatory, allergic, and autoimmune diseases.For example, the compounds are useful to treat, prevent or managediseases including, but not limited to, HIV; hepatitis; adultrespiratory distress syndrome; bone-resorption diseases; chronicobstructive pulmonary disease, chronic pulmonary inflammatory diseases;dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock;hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury;meningitis; psoriasis; fibrotic disease; cachexia; graft rejection;auto-immune disease; rheumatoid spondylitis; arthritic conditions, suchas rheumatoid arthritis and osteoarthritis; osteoporosis, Parkinson'sDisease, Crohn's disease; ulcerative colitis; inflammatory-boweldisease; multiple sclerosis; systemic lupus erythrematosus; ENL inleprosy; radiation damage; asthma; and hyperoxic alveolar injury.

The compounds of the invention are also useful for treating, preventingor managing bacterial infections including, but not limited to, malaria,mycobacterial infection, and opportunistic infections resulting fromHIV.

Another embodiment of the invention encompasses methods of treating,managing or preventing diseases and disorders associated with, orcharacterized by, undesired angiogenesis, which comprise administeringto a patient in need of such treatment, management or prevention atherapeutically or prophylactically effective amount of a compound ofthe invention, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle), which are mediated byundesired or uncontrolled angiogenesis.

Other examples include, but are not limited to, diabetic retinopathy,retinopathy of prematurity, corneal graft rejection, neovascularglaucoma, retrolental fibroplasia, proliferative vitreoretinopathy,trachoma, myopia, optic pits, epidemic keratoconjunctivitis, atopickeratitis, superior limbic keratitis, pterygium keratitis sicca,sjogrens, acne rosacea, phylectenulosis, syphilis, lipid degeneration,bacterial ulcer, fungal ulcer, Herpes simplex infection, Herpes zosterinfection, protozoan infection, Kaposi sarcoma, Mooren ulcer, Terrien'smarginal degeneration, mariginal keratolysis, rheumatoid arthritis,systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis, scleritis,Steven's Johnson disease, periphigoid radial keratotomy, sickle cellanemia, sarcoid, pseudoxanthoma elasticum, Pagets disease, veinocclusion, artery occlusion, carotid obstructive disease, chronicuveitis, chronic vitritis, Lyme's disease, Eales disease, Bechet'sdisease, retinitis, choroiditis, presumed ocular histoplasmosis, Bestsdisease, Stargarts disease, pars planitis, chronic retinal detachment,hyperviscosity syndromes, toxoplasmosis, rubeosis, sarcodisis,sclerosis, soriatis, psoriasis, primary sclerosing cholangitis,proctitis, primary biliary srosis, idiopathic pulmonary fibrosis,alcoholic hepatitis, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, malignancy-associated hypercalcemia, stroke,circulatory shock, periodontitis, gingivitis, macrocytic anemia,refractory anemia, 5q-syndrome, and veterinary disorder caused by felineimmunodeficiency virus, equine infectious anemia virus, caprinearthritis virus, visna virus, maedi virus or lenti virus.

In certain embodiment of the invention, specific diseases do not includecongestive heart failure, cardiomyopathy, pulmonary edema,endotoxin-mediated septic shock, acute viral myocarditis, cardiacallograft rejection, myocardial infarction, HIV, hepatitis, adultrespiratory distress syndrome, bone-resorption disease, chronicobstructive pulmonary diseases, chronic pulmonary inflammatory disease,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft rejection,rheumatoid spondylitis, osteoporosis, Parkinson's Disease, Crohn'sdisease, ulcerative colitis, inflammatory-bowel disease, multiplesclerosis, systemic lupus erythrematosus, erythema nodosum leprosum inleprosy, radiation damage, asthma, hyperoxic alveolar injury, malariaand mycobacterial infection.

The compounds of the invention are also useful for preventing heartdisease, such as congestive heart failure, cardiomyopathy, pulmonaryedema, endotoxin-mediated septic shock, acute viral myocarditis, cardiacallograft rejection, and myocardial infarction.

The compounds of the invention are also useful for treating, preventingor managing MDS and related syndromes, such as, but not limited to,refractory anemia (RA), RA with ringed sideroblasts (RARS), RA withexcess blasts (RAEB), RAEB in transformation (RAEB-T), chronicmyelomonocytic leukemia (CMML), and symptoms such as anemia,thrombocytopenia, neutropenia, cytopenias, bicytopenia (two deficientcell lines), and pancytopenia (three deficient cell lines).

The compounds of the invention are also useful for treating, preventingor managing CRPS and related syndromes. As used herein, and unlessotherwise specified, the term “CRPS” refers to a chronic pain disordercharacterized by one or more of the following: pain, whether spontaneousor evoked, including allodynia (painful response to a stimulus that isnot usually painful) and hyperalgesia (exaggerated response to astimulus that is usually only mildly painful); pain that isdisproportionate to the inciting event (e.g., years of severe pain afteran ankle sprain); regional pain that is not limited to a singleperipheral nerve distribution; and autonomic dysregulation (e.g., edema,alteration in blood flow and hyperhidrosis) associated with trophic skinchanges (hair and nail growth abnormalities and cutaneous ulceration).Unless otherwise indicated, the terms “complex regional pain syndrome,”“CRPS” and “CRPS and related syndromes” include: type I, encompassingthe condition known as reflex sympathetic dystrophy (RSD), which occursafter an initial noxious event other than a nerve injury; type II,encompassing the condition known as causalgia, which occurs after nerveinjury; acute stage (usually hyperthermic phase of 2–3 months);dystrophic phase (showing vasomotor instability for several months);atrophic phase (usually cold extremity with atrophic changes); reflexneurovascular dystrophy; reflex dystrophy; sympathetic maintained painsyndrome; Sudeck atrophy of bone; algoneurodystrophy; shoulder handsyndrome; post-traumatic dystrophy; trigeminal neuralgia; post herpeticneuralgia; cancer related pain; phantom limb pain; fibromyalgia; chronicfatigue syndrome; radiculopathy; and other painful neuropathicconditions, e.g., diabetic neuropathy, luetic neuropathy, or painfulneuropathic condition iatrogenically induced from drugs such asvincristine, velcade and thalidomide.

The compounds of the invention are useful for treating, preventing ormanaging all types of CRPS and related syndromes, including, but notlimited to, those referred to as CRPS type I, CRPS type II, reflexsympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflexdystrophy, sympathetically maintained pain syndrome, causalgia, Sudeckatrophy of bone, algoneurodystrophy, shoulder hand syndrome,post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia,cancer related pain, phantom limb pain, fibromyalgia, chronic fatiguesyndrome, post-operative pain, spinal cord injury pain, centralpost-stroke pain, radiculopathy, and other painful neuropathicconditions, e.g., diabetic neuropathy.

The compounds of the invention are also useful for treating, preventingand managing MD and related syndromes, such as, but not limited to,atrophic (dry) MD, exudative (wet) MD, age-related maculopathy (ARM),choroidal neovascularisation (CNVM), retinal pigment epitheliumdetachment (PED), and atrophy of retinal pigment epithelium (RPE).

As used herein, the term macular degeneration (MD) encompasses all formsof macular degenerative diseases regardless of a patient's age, althoughsome macular degenerative diseases are more common in certain agegroups. These include, but are not limited to, Best's disease orvitelliform (most common in patients under about 7 years of age);Stargardt's disease, juvenile macular dystrophy or fundus flavimaculatus(most common in patients between about 5 and about 20 years of age);Behr's disease, Sorsby's disease, Doyne's disease or honeycomb dystrophy(most common in patients between about 30 and about 50 years of age);and age-related macular degeneration (most common in patients of about60 years of age or older).

Symptoms associated with MD and related syndromes include, but are notlimited to, drusen rounded whitish-yellowish spots in the fundus,submacular disciform scar tissue, choroidal neovascularisation, retinalpigment epithelium detachment, atrophy of retinal pigment epithelium,abnormal blood vessels stemming from the choroid (the blood vessel-richtissue layer just beneath the retina), a blurry or distorted area ofvision, a central blind spot, pigmentary abnormalities, a continuouslayer of fine granular material deposited in the inner part of Bruch'smembrane, and a thickening and decreased permeability of Bruch'smembrane.

Causes of MD include, but are not limited to, genetic, physical trauma,diseases such as diabetes, and infection, such as bacterial infection(e.g., leprosy and ENL in particular). The compounds of the inventioncan effectively treat, prevent or manage all types of MD and relatedsyndromes or symptoms, regardless of their causes.

The compounds of the invention are also useful for treating, preventingor managing all types of MPD and related syndromes or symptoms. Examplesof MPD that can be treated, prevented or managed by the compounds of theinvention include, but are not limited to, polycythemia rubra vera(PRV), primary thromobocythemia (PT), chronic myelogenous leukemia(CML), and agnogenic myeloid metaplasia (AMM).

As used herein, the term “myeloproliferative disease,” or “MPD,” means ahematopoietic stem cell disorder characterized by one or more of thefollowing: clonal expansion of a multipotent hematopoietic progenitorcell with the overproduction of one or more of the formed elements ofthe blood (e.g., elevated red blood cell count, elevated white bloodcell count, and/or elevated platelet count), presence of Philadelphiachromosome or bcr-abl gene, teardrop poikilocytosis on peripheral bloodsmear, leukoerythroblastic blood pictuer, giant abnormal platelets,hypercellular bone marrow with reticular or collagen fibrosis, markedleft-shifted myeloid series with a low percentage of promyelocytes andblasts, splenomegaly, thrombosis, risk of progression to acute leukemiaor cellular marrow with impaired morphology. The term“myeloproliferative disease,” or “MPD,” unless otherwise noted,includes: polycythemia rubra vera (PRV), primary thromobocythemia (PT),chronic myelogenous leukemia (CML), and agnogenic myeloid metaplasia(AMM).

Symptoms associated with MPD include, but are not limited to, headache,dizziness, tinnitus, blurred vision, fatigue, night sweat, low-gradefever, generalized pruritus, epistaxis, blurred vision, splenomegaly,abdominal fullness, thrombosis, increased bleeding, anemia, splenicinfarction, severe bone pain, hematopoiesis in the liver, ascites,esophageal varices, liver failure, respiratory distress, and priapism.Laboratory findings associated with MPD include, but are not limited to,clonal expansion of a multipotent hematopoietic progenitor cell with theoverproduction of one or more of the formed elements of the blood (e.g.,elevated red blood cell count, elevated white blood cell count, and/orelevated platelet count), presence of Philadelphia chromosome or bcr-ablgene, teardrop poikilocytosis on peripheral blood smear,leukoerythroblastic blood pictuer, giant abnormal platelets,hypercellular bone marrow with reticular or collagen fibrosis, andmarked left-shifted myeloid series with a low percentage ofpromyelocytes and blasts.

The compounds of the invention are also useful for treating, preventingand managing all tyoes of CNS disorders. Examples of CNS disordersinclude, but are not limited to, Parkinson disease; Alzheimer disease,mild cognitive impairment; depression; defective long-term memory;Amyotrophic Lateral Sclerosis (ALS); CNS trauma; hypokinetic disorders;bradykinesia; slowness of movement; paucity of movement; impairment ofdexterity; hypophonia; monotonic speech; muscular rigidity; maskedfaces; decreased blinking; stooped posture; decreased arm swinging whenwalking; micrographia; parkinsonian tremor; parkinsonian gait; posturalinstability; festinating gait; motion freezing; disturbances ofcognition, mood, sensation, sleep or autonomic function; dementia; andsleep disorders.

In a specific embodiment, the central nervous system disorder to beprevented, treated and/or managed is Parkinson disease, Alzheimerdisease, mild cognitive impairment, dementia, depression, defectivelong-term memory, Amyotrophic Lateral Sclerosis (ALS) or CNS trauma.

The invention encompasses methods of treating, preventing or managingcentral nervous system disorders, preferably Parkinson disease orAlzheimer disease. In one embodiment, the methods of the invention areused to treat, prevent or manage disorders related to movement,including, but not limited to, slow execution or bradykinesia, paucityof movement or akinesia, movement disorders that impair fine motorcontrol and finger dexterity, and other manifestations of bradykinesia,such as, but not limited to, hypophonia and monotonic speech. In anotherembodiment, the methods of the invention are used to treat, prevent ormanage disorders related to muscular rigidity, including, but notlimited to, a uniform increase in resistance to passive movement,interruptions to passive movement, and combinations of rigidity anddystonia. In a specific embodiment, methods of the invention are used totreat inflammation associated with Parkinson or related disease. In yetanother embodiment of the invention, disorders resembling Parkinsoniantremor are treated, prevented or managed by the methods of theinvention, including but not limited to, tremors of the face, jaw,tongue, posture, and other tremors that are present at rest and thatattenuate during movement. In another embodiment, the methods of theinvention are used to treat, prevent or manage disorders in gait,including, but not limited to, those resembling parkinsonian gait,shuffling, short steps, a tendency to turn en bloc, and festinatinggait. In another embodiment of the invention, nonmotor symptoms aretreated, prevented or managed using the methods of the invention,including, but not limited to, disorders of mood, cognition, defectivelong-term memory, sensation, sleep, dementia, and depression. In otherembodiment of the invention, secondary forms of parkinsonism aretreated, prevented or managed by the methods of the invention,including, but not limited to, drug induced parkinsonism, vascularparkinsonism, multiple system atrophy, progressive supranuclear palsy,disorders with primary tau pathology, cortical basal gangliadegeneration, parkinsonism with dementia, hyperkinetic disorders,chorea, Huntington disease, dystonia, Wilson disease, Tourette syndrome,essential tremor, myoclonus, and tardive movement disorders. In otherembodiment of the invention, other central nervous system disorders aretreated, prevented or managed by the methods of the invention,including, but not limited to, Alzheimer disease, mild cognitiveimpairment, Amyotrophic Lateral Sclerosis (ALS) and CNS trauma.

The compounds of the invention are also useful for treating, preventingor managing an asbestos-related disease or disorder and relatedsymptoms. Examples of asbestos-related diseases or disorders include,but are not limited to, malignant mesothelioma, asbestosis, malignantpleural effusion, benign pleural effusion, pleural plaque, pleuralcalcification, diffuse pleural thickening, round atelectasis, andbronchogenic carcinoma. It further encompasses methods of treatingpatients who have been previously treated for asbestos-related diseasesor disorders but were not sufficiently responsive or werenon-responsive, as well as those who have not previously been treatedfor the diseases or disorders. Because patients have heterogenousclinical manifestations and varying clinical outcomes, the treatmentgiven to a patient may vary, depending on his/her prognosis. The skilledclinician will be able to readily determine without undueexperimentation specific secondary agents and types of physical therapythat can be effectively used to treat an individual patient.

Symptoms of asbestos-related diseases or disorders include, but are notlimited to, dyspnea, obliteration of the diaphragm, radiolucentsheet-like encasement of the pleura, pleural effusion, pleuralthickening, decreased size of the chest, chest discomfort, chest pain,easy fatigability, fever, sweats and weight loss. Examples of patientsat risk of asbestos-related diseases or disorders include, but are notlimited to, those who have been exposed to asbestos in the workplace andtheir family members who have been exposed to asbestos embedded in theworker's clothing. Patients having familial history of asbestos-relateddiseases or disorders are also preferred candidates for preventiveregimens.

4.4. Pharmaceutical Formulations

Administration of compounds of the invention can be systemic or local.In most instances, administration to a mammal will result in systemicrelease of the compounds of the invention (i.e., into the bloodstream).Methods of administration include enteral routes, such as oral, buccal,sublingual, and rectal; topical administration, such as transdermal andintradermal; and parenteral administration. Suitable parenteral routesinclude injection via a hypodermic needle or catheter, for example,intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal,intraarterial, intraventricular, intrathecal, and intracameral injectionand non-injection routes, such as intravaginal rectal, or nasaladministration. Preferably, the compounds and compositions of theinvention are administered orally. In specific embodiments, it may bedesirable to administer one or more compounds of the invention locallyto the area in need of treatment. This may be achieved, for example, bylocal infusion during surgery, topical application, e.g., in conjunctionwith a wound dressing after surgery, by injection, by means of acatheter, by means of a suppository, or by means of an implant, saidimplant being of a porous, non-porous, or gelatinous material, includingmembranes, such as sialastic membranes, or fibers.

The compounds of the invention can be administered via typical as wellas non-standard delivery systems, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc. For example, the compoundsand compositions of the invention can be delivered in a vesicle, inparticular a liposome (see Langer, 1990, Science 249:1527–1533; Treat etal., in Liposomes in Therapy of Infectious Disease and Cancer,Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353–365 (1989);Lopez-Berestein, ibid., pp. 317–327; see generally ibid.). In anotherexample, the compounds and compositions of the invention can bedelivered in a controlled release system. In one embodiment, a pump maybe used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engl. J. Med. 321:574). In another example, polymeric materials can beused (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Press., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105). In still another example, a controlled-releasesystem can be placed in proximity of the target area to be treated,e.g., the liver, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115–138 (1984)). Other controlled-release systemsdiscussed in the review by Langer, 1990, Science 249:1527–1533) can beused.

When administered as a composition, a compound of the invention will beformulated with a suitable amount of a pharmaceutically acceptablevehicle or carrier so as to provide the form for proper administrationto the mammal. The term “pharmaceutically acceptable” means approved bya regulatory agency of the Federal or a state government or listed inthe U.S. Pharmacopeia or other generally recognized pharmacopeia for usein mammals, and more particularly in humans. The term “vehicle” refersto a diluent, adjuvant, excipient, or carrier with which a compound ofthe invention is formulated for administration to a mammal. Suchpharmaceutical vehicles can be liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating and coloring agents maybe used. Preferably, when administered to a mammal, the compounds andcompositions of the invention and pharmaceutically acceptable vehicles,excipients, or diluents are sterile. An aqueous medium is a preferredvehicle when the compound of the invention is administeredintravenously, such as water, saline solutions, and aqueous dextrose andglycerol solutions.

The present compounds and compositions can take the form of capsules,tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs,solutions, suspensions, emulsions, suppositories, or sustained-releaseformulations thereof, or any other form suitable for administration to amammal. In a preferred embodiment, the compounds and compositions of theinvention are formulated for administration in accordance with routineprocedures as a pharmaceutical composition adapted for oral orintravenous administration to humans. In one embodiment, thepharmaceutically acceptable vehicle is a hard gelatin capsule. Examplesof suitable pharmaceutical vehicles and methods for formulation thereofare described in Remington: The Science and Practice of Pharmacy,Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995,Chapters 86, 87, 88, 91, and 92, incorporated herein by reference.

Compounds and compositions of the invention formulated for oraldelivery, are preferably in the form of capsules, tablets, pills, or anycompressed pharmaceutical form. Moreover, where in tablet or pill form,the compounds and compositions may be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compounds and compositions of the invention. Inthese later platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound that swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time delay materialsuch as glycerol monostearate or glycerol stearate may also be used.Oral compositions can include standard vehicles, excipients, anddiluents, such as magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, lactose, dextrose, sucrose, sorbitol, mannitol,starch, gum acacia, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidinone, water, syrup, and methyl cellulose, theformulations can additionally include lubricating agents, such as talc,magnesium stearate, mineral oil, wetting agents, emulsifying andsuspending agents, preserving agents such as methyl- andpropylhydroxybenzoates. Such vehicles are preferably of pharmaceuticalgrade. Orally administered compounds and compositions of the inventioncan optionally include one or more sweetening agents, such as fructose,aspartame or saccharin; one or more flavoring agents such as peppermint,oil of wintergreen, or cherry; or one or more coloring agents to providea pharmaceutically palatable preparation.

A therapeutically effective dosage regimen for the treatment of aparticular disorder or condition will depend on its nature and severity,and can be determined by standard clinical techniques according to thejudgment of a medical practitioner. In addition, in vitro or in vivoassays can be used to help identify optimal dosages. Of course, theamount of a compound of the invention that constitutes a therapeuticallyeffective dose also depends on the administration route. In general,suitable dosage ranges for oral administration are about 0.001milligrams to about 20 milligrams of a compound of the invention perkilogram body weight per day, preferably, about 0.7 milligrams to about6 milligrams, more preferably, about 1.5 milligrams to about 4.5milligrams. In a preferred embodiment, a mammal, preferably, a human isorally administered about 0.01 mg to about 1000 mg of a compound of theinvention per day, more preferably, about 0.1 mg to about 300 mg perday, or about 1 mg to about 100 mg in single or divided doses. Thedosage amounts described herein refer to total amounts administered;that is, if more than one compound of the invention is administered, thepreferred dosages correspond to the total amount of the compounds of theinvention administered. Oral compositions preferably contain 10% to 95%of a compound of the invention by weight. Preferred unit oral-dosageforms include pills, tablets, and capsules, more preferably capsules.Typically such unit-dosage forms will contain about 0.01 mg, 0.1 mg, 1mg, 5 mg, 10 mg, 15 mg, 20 mg, 50 mg, 100 mg, 250 mg, or 500 mg of acompound of the invention, preferably, from about 5 mg to about 200 mgof compound per unit dosage.

In another embodiment, the compounds and compositions of the inventioncan be administered parenterally (e.g., by intramuscular, intrathecal,intravenous, and intraarterial routes), preferably, intravenously.Typically, compounds and compositions of the invention for intravenousadministration are solutions in sterile isotonic aqueous vehicles, suchas water, saline, Ringer's solution, or dextrose solution. Wherenecessary, the compositions may also include a solubilizing agent.Compositions for intravenous administration may optionally include alocal anesthetic such as lignocaine to ease pain at the site of theinjection. For intravenous administration, the compounds andcompositions of the invention can be supplied as a sterile, drylyophilized powder or water-free concentrate in a hermetically sealedcontainer, such as an ampule or sachette, the container indicating thequantity of active agent. Such a powder or concentrate is then dilutedwith an appropriate aqueous medium prior to intravenous administration.An ampule of sterile water, saline solution, or other appropriateaqueous medium can be provided with the powder or concentrate fordilution prior to administration. Or the compositions can be supplied inpre-mixed form, ready for administration. Where a compound orcomposition of the invention is to be administered by intravenousinfusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical-grade water, saline, or other suitablemedium.

Rectal administration can be effected through the use of suppositoriesformulated from conventional carriers such as cocoa butter, modifiedvegetable oils, and other fatty bases. Suppositories can be formulatedby well-known methods using well-known formulations, for example seeRemington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed.,Mack Publishing Co. Easton, Pa., 19th ed., 1995, pp. 1591–1597,incorporated herein by reference

To formulate and administer topical dosage forms, well-known transdermaland intradermal delivery mediums such as lotions, creams, and ointmentsand transdermal delivery devices such as patches can be used (Ghosh, T.K.; Pfister, W. R.; Yum, S. I. Transdermal and Topical Drug DeliverySystems, Interpharm Press, Inc. p. 249–297, incorporated herein byreference). For example, a reservoir type patch design can comprise abacking film coated with an adhesive, and a reservoir compartmentcomprising a compound or composition of the invention, that is separatedfrom the skin by a semipermeable membrane (e.g., U.S. Pat. No.4,615,699, incorporated herein by reference). The adhesive coatedbacking layer extends around the reservoir's boundaries to provide aconcentric seal with the skin and hold the reservoir adjacent to theskin.

Mucosal dosage forms of the invention include, but are not limited to,ophthalmic solutions, sprays and aerosols, or other forms known to oneof skill in the art. See, e.g., Remington's Pharmaceutical Sciences,18th eds., Mack Publishing, Easton Pa. (1990); and Introduction toPharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia(1985). Dosage forms suitable for treating mucosal tissues within theoral cavity can be formulated as mouthwashes or as oral gels. In oneembodiment, the aerosol comprises a carrier. In another embodiment, theaerosol is carrier free.

The compounds of the invention may also be administered directly to thelung by inhalation. For administration by inhalation, a compound of theinvention can be conveniently delivered to the lung by a number ofdifferent devices. For example, a Metered Dose Inhaler (“MDI”) whichutilizes canisters that contain a suitable low boiling propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas can beused to deliver a compound of formula I directly to the lung. MDIdevices are available from a number of suppliers such as 3M Corporation,Aventis, Boehringer Ingleheim, Forest Laboratories, Glaxo-Wellcome,Schering Plough and Vectura.

Alternatively, a Dry Powder Inhaler (DPI) device can be used toadminister a compound of the invention to the lung (See, e.g., Raleighet al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40,397, which is herein incorporated by reference). DPI devices typicallyuse a mechanism such as a burst of gas to create a cloud of dry powderinside a container, which can then be inhaled by the patient. DPIdevices are also well known in the art and can be purchased from anumber of vendors which include, for example, Fisons, Glaxo-Wellcome,Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. Apopular variation is the multiple dose DPI (“MDDPI”) system, whichallows for the delivery of more than one therapeutic dose. MDDPI devicesare available from companies such as AstraZeneca, GlaxoWellcome, IVAX,Schering Plough, SkyePharma and Vectura. For example, capsules andcartridges of gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch for these systems.

Another type of device that can be used to deliver a compound of theinvention to the lung is a liquid spray device supplied, for example, byAradigm Corporation. Liquid spray systems use extremely small nozzleholes to aerosolize liquid drug formulations that can then be directlyinhaled into the lung.

In a preferred embodiment, a nebulizer device is used to deliver acompound of the invention to the lung. Nebulizers create aerosols fromliquid drug formulations by using, for example, ultrasonic energy toform fine particles that can be readily inhaled (See e.g., Verschoyle etal., British J Cancer, 1999, 80, Suppl 2, 96, which is hereinincorporated by reference). Examples of nebulizers include devicessupplied by Sheffield/Systemic Pulmonary Delivery Ltd. (See, Armer etal., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No.5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974, which areherein incorporated by reference), Aventis and Batelle PulmonaryTherapeutics

In a particularly preferred embodiment, an electrohydrodynamic (“EHD”)aerosol device is used to deliver a compound of the invention to thelung. EHD aerosol devices use electrical energy to aerosolize liquiddrug solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No.4,765,539; Coffee, U.S. Pat. No., 4,962,885; Coffee, PCT Application, WO94/12285; Coffee, PCT Application, WO 94/14543; Coffee, PCT Application,WO 95/26234, Coffee, PCT Application, WO 95/26235, Coffee, PCTApplication, WO 95/32807, which are herein incorporated by reference).The electrochemical properties of the formulation containing compoundsof the invention may be important parameters to optimize when deliveringthis drug to the lung with an EHD aerosol device and such optimizationis routinely performed by one of skill in the art. EHD aerosol devicesmay more efficiently delivery drugs to the lung than existing pulmonarydelivery technologies. Other methods of intra-pulmonary delivery will beknown to the skilled artisan and are within the scope of the invention.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include apharmaceutically acceptable carrier. Preferably, the pharmaceuticallyacceptable carrier is a liquid such as alcohol, water, polyethyleneglycol or a perfluorocarbon. Optionally, another material may be addedto alter the aerosol properties of the solution or suspension of acompound of the invention. Preferably, this material is liquid such asan alcohol, glycol, polyglycol or a fatty acid. Other methods offormulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (See, e.g.,Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611,which are herein incorporated by reference). A compound of the inventioncan also be formulated in rectal or vaginal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, a compound of theinvention can also be formulated as a depot preparation. Such longacting formulations can be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds can be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well known examples of delivery vehiclesthat can be used to deliver compounds of the inventions. Certain organicsolvents such as dimethylsulfoxide can also be employed, althoughusually at the cost of greater toxicity. A compound of the invention canalso be delivered in a controlled release system. In one embodiment, apump can be used (Sefton, CRC Crit. Ref Biomed Eng., 1987, 14, 201;Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N. Engl. J Med,1989, 321, 574). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, J Macromol. Sci. Rev. Macromol. Chem.,1983, 23, 61; see also Levy et al., Science 1985, 228, 190; During etal., Ann. Neurol., 1989, 25, 351; Howard et al., 1989, J. Neurosurg. 71,105). In yet another embodiment, a controlled-release system can beplaced in proximity of the target of the compounds of the invention,e.g., the lung, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115 (1984)). Other controlled-release system can beused (see e.g. Langer, Science, 1990, 249, 1527).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide mucosal dosage forms encompassed by thisinvention are well known to those skilled in the pharmaceutical arts,and depend on the particular site or method which a given pharmaceuticalcomposition or dosage form will be administered. With that fact in mind,typical excipients include, but are not limited to, water, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof, which arenon-toxic and pharmaceutically acceptable. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, canalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

The invention also provides pharmaceutical packs or kits comprising oneor more containers filled with one or more compounds of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In one embodiment, the kit contains more than onecompound of the invention. In another embodiment, the kit comprises acompound of the invention and another biologically active agent.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetheradministration of a specific compound of the invention or a combinationof compounds of the invention is preferred. The compounds andcompositions of the invention may also be demonstrated to be effectiveand safe using animal model systems. Other methods will be known to theskilled artisan and are within the scope of the invention.

4.5. Combination Therapy

In certain embodiments, a compound of the invention is administered to amammal, preferably, a human concurrently with one or more othertherapeutic agents, or with one or more other compounds of theinvention, or with both. By “concurrently,” it is meant that a compoundof the invention and the other agent are administered to a mammal in asequence and within a time interval such that the compound of theinvention can act together with the other agent to provide an increasedor synergistic benefit than if they were administered otherwise. Forexample, each component may be administered at the same time orsequentially in any order at different points in time; however, if notadministered at the same time, they should be administered sufficientlyclosely in time so as to provide the desired treatment effect.Preferably, all components are administered at the same time, and if notadministered at the same time, preferably, they are all administeredfrom about 6 hours to about 12 hours apart from one another.

When used in combination with other therapeutic agents, the compounds ofthe invention and the therapeutic agent can act additively or, morepreferably, synergistically. In one embodiment, a compound or acomposition of the invention is administered concurrently with anothertherapeutic agent in the same pharmaceutical composition. In anotherembodiment, a compound or a composition of the invention is administeredconcurrently with another therapeutic agent in separate pharmaceuticalcompositions. In still another embodiment, a compound or a compositionof the invention is administered prior or subsequent to administrationof another therapeutic agent. As many of the disorders for which thecompounds and compositions of the invention are useful in treating arechronic disorders, in one embodiment combination therapy involvesalternating between administering a compound or a composition of theinvention and a pharmaceutical composition comprising anothertherapeutic agent, e.g., to minimize the toxicity associated with aparticular drug. In certain embodiments, when a composition of theinvention is administered concurrently with another therapeutic agentthat potentially produces adverse side effects including, but notlimited to toxicity, the therapeutic agent can advantageously beadministered at a dose that falls below the threshold that the adverseside effect is elicited. Additional therapeutic agents include, but arenot limited to, hematopoietic growth factors, cytokines, anti-canceragents, antibiotics, immunosuppressive agents, steroids, antihistamines,lukatriene inhibitors and other therapeutics discussed herein.

Preferred additional therapeutic agents include, but are not limited to,Remicade™, docetaxel, Celecoxib™, melphalan, dexamethasone, steroids,gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide,temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan,methotrexate, Arisa®, Taxol™, taxotere, fluorouracil, leucovorin,irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferonalpha, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine,IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate,biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, PEGINTRON-A, doxil, vincristine, decadron, doxorubicin, paclitaxel,ganciclovir, adriamycin, estramustine, Emcyt, sulindac, and etoposide.

The invention further encompasses mutants and derivatives (e.g.,modified forms) of naturally occurring proteins that exhibit, in vivo,at least some of the pharmacological activity of the proteins upon whichthey are based. Examples of mutants include, but are not limited to,proteins that have one or more amino acid residues that differ from thecorresponding residues in the naturally occurring forms of the proteins.Also encompassed by the term “mutants” are proteins that lackcarbohydrate moieties normally present in their naturally occurringforms (e.g., nonglycosylated forms). Examples of derivatives include,but are not limited to, pegylated derivatives and fusion proteins, suchas proteins formed by fusing IgG1 or IgG3 to the protein or activeportion of the protein of interest. See, e.g., Penichet, M. L. andMorrison, S. L., J. Immunol. Methods 248:91–101 (2001).

Recombinant and mutated forms of G-CSF can be prepared as described inU.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all ofwhich are incorporated herein by reference. Recombinant and mutatedforms of GM-CSF can be prepared as described in U.S. Pat. Nos.5,391,485; 5,393,870; and 5,229,496; all of which are incorporatedherein by reference. In fact, recombinant forms of G-CSF and GM-CSF arecurrently sold in the United States for the treatment of symptomsassociated with specific chemotherapies. A recombinant form of G-CSFknown as filgrastim is sold in the United States under the trade nameNEUPOGEN®, and is indicated to decrease the incidence of infection, asmanifested by febrile neutropenia, in patients with nonmyeloidmalignancies receiving myelosuppressive anti-cancer drugs associatedwith a significant incidence of severe neutropenia with fever.Physicians' Desk Reference, 587–592 (56^(th) ed., 2002). A recombinantform of GM-CSF known as sargramostim is also sold in the United Statesunder the trade name LEUKINE®. LEUKINE® is indicated for use followinginduction chemotherapy in older adult patients with acute myelogenousleukemia (AML) to shorten time to neutrophil recovery. Physicians' DeskReference, 1755–1760 (56^(th) ed., 2002). A recombinant form of EPOknown as epoetin alfa is sold in the United States under the trade nameEPOGEN®. EPOGEN® is used to stimulate red cell production by stimulatingdivision and maturation of committed red cell precursor cells.Physicians'Desk Reference, 582–587 (56^(th) ed., 2002).

A growth-factor or cytokine such as G-CSF, GM-CSF and EPO can also beadministered in the form of a vaccine. For example, vaccines thatsecrete, or cause the secretion of, cytokines such as G-CSF and GM-CSFcan be used in the methods, pharmaceutical compositions, and kits of theinvention. See, e.g., Emens, L. A., et al., Curr. Opinion Mol. Ther.3(1):77–84 (2001).

Examples of anti-cancer drugs that can be used in the variousembodiments of the invention, including the methods, dosing regimens,cocktails, pharmaceutical compositions and dosage forms and kits of theinvention, include, but are not limited to: acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; dacarbazine; docetaxel; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interleukin II (including recombinant interleukin II, or rIL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin;irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole;leuprolide acetate; liarozole hydrochloride; lometrexol sodium;lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride. Other anti-cancer drugs include, but are not limited to:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole;cartilage derived inhibitor; carzelesin; casein kinase inhibitors(ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemrnin B; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol;dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epristeride; estramustineanalogue; estrogen agonists; estrogen antagonists; etanidazole;etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide;filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathioneinhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;ilomastat; imiquimod; immunostimulant peptides; insulin-like growthfactor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim;Erbitux, human chorionic gonadotrophin; mopidamol; mustardanticancer agent; mycaperoxide B; mycobacterial cell wall extract;myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim;nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitricoxide modulators; nitroxide antioxidant; nitrullyn; O⁶-benzylguanine;octreotide; okicenone; oligonucleotides; onapristone; ondansetron;ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxelderivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; rasinhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide;roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescencederived inhibitor 1; sense oligonucleotides; signal transductioninhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodiumphenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

In one embodiment of the invention, the compounds of the invention canbe used, not only to directly treat the disorder, but also to reduce thedose or toxicity of another chemotherapeutic. For example, the compoundsof the invention can be administered to reduce gastrointestinal toxicityassociated with a topoisomerase inhibitor, such as irinotecan.

4.6. Biological Assays

Compounds having PDE 4, TNF-α, and MMP inhibitory activity can beassayed using methods commonly known in the art including, but notlimited to, enzyme immunoassay, radioimmunoassay, immunoelectrophoresis,and affinity labeling. Further assays which can be utilized includeLPS-induced TNF and PDE4 enzymatic assays and the methods set out inInternational Patent Publication Nos. WO 01/90076 A1 WO 01/34606 A1 eachof which are incorporated herein in their entireties by reference.

PBMC from normal donors are obtained by Ficoll-Hypaque densitycentrifugation. Cells are cultured in RPMI supplemented with 10%,AB+serum, 2 mM L-glutamine, 100 U/mL penicillin and 100 mg/mLstreptomycin.

The test compounds are dissolved in dimethylsulfoxide (Sigma Chemical),further dilutions are done in supplemented RPMI. The finaldimethylsulfoxide concentration in the presence or absence of drug inthe PBMC suspensions is 0.25 wt %. The test compounds are assayed athalf-log dilutions starting in 50 mg/mL. The test compounds are added toPBMC (10⁶ cells/mL) in 96 wells plates one hour before the addition ofLPS.

PBMC (10⁶ cells/mL) in the presence or absence of test compounds arestimulated by treatment with 1 mg/mL of LPS from Salmonella minnesotaR595 (List Biological Labs, Campbell, Calif.). Cells are then incubatedat 37° C. for 18–20 hours. Supernatants are harvested and assayedimmediately for TNFα levels or kept frozen at −70° C. (for not more than4 days) until assayed.

The concentration of TNFα in the supernatant is determined by human TNFαELISA kits (ENDOGEN, Boston, Mass.) according to the manufacturer'sdirections.

Phosphodiesterase can be determined in conventional models. For example,using the method of Hill and Mitchell, U937 cells of the humanpromonocytic cell line are grown to 1×10⁶ cells/mL and collected bycentrifugation. A cell pellet of 1×10⁹ cells is washed in phosphatebuffered saline and then frozen at −70° C. for later purification orimmediately lysed in cold homogenization buffer (20 mM Tris-HCl, pH 7.1,3 mM 2-mercaptoethanol, 1 mM magnesium chloride, 0.1 mM ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 1 μMphenyl-methylsulfonyl fluoride (PMSF), and 1 μg/mL leupeptin). Cells arehomogenized with 20 strokes in a Dounce homogenizer and supernatantcontaining the cytosolic fraction are obtained by centrifugation. Thesupernatant then is loaded onto a Sephacryl S-200 column equilibrated inhomogenization buffer. Phosphodiesterase is eluted in homogenizationbuffer at a rate of approximately 0.5 mL/min and fractions are assayedfor phosphodiesterase activity −/+roliprarn. Fractions containingphosphodiester-ase activity (rolipram sensitive) are pooled andaliquoted for later use.

The phosphodiesterase assay is carried out in a total volume of 100 μlcontaining various concentration of test compounds, 50 mM Tris-HCl, pH7.5, 5 mM magnesium chloride, and 1 μM cAMP of which 1% was ³H cAMP.Reactions are incubated at 30° C. for 30 minutes and terminated byboiling for 2 minutes. The amount of phosphodiesterase IV containingextract used for these experiments is predetermined such that reactionsare within the linear range and consumed less than 15% of the totalsubstrate. Following termination of reaction, samples are chilled at 4°C. and then treated with 10 μl 10 mg/mL snake venom for 15 min at 30° C.Unused substrate then is removed by adding 200 μl of a quaternaryammonium ion exchange resin (AG1-X8, BioRad) for 15 minutes. Samplesthen are spun at 3000 rpm, 5 min and 50 μl of the aqueous phase aretaken for counting. Each data point is carried out in duplicate andactivity is expressed as percentage of control. The IC₅₀ of the compoundthen is determined from dose response curves of a minimum of threeindependent experiments.

The following examples are offered by way of illustration and are notintended to limit the scope of the invention.

5. EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Bruker AC 250 MHz NMR spectrometer.Significant peaks are tabulated in the order: chemical shift,multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) andnumber of protons.

5.1. Example 1 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

A solution of (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol(1.1 g, 4.9 mmol), 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoicacid methyl ester (1.5 g, 4.8 mmol) and triethylamine (0.75 mL, 5.4mmol) in DMF (10 mL) was heated at 100° C. for 18 hrs. The solvent wasremoved in vacuo. The residue was extracted with ethyl acetate (50 mL)and water (50 mL). The organic layer was washed with HCl (1N, 50 mL),brine (50 mL), and dried over MgSO₄. The solvent was removed in vacuo togive an oil. The oil was stirred in ether (5 mL) and hexane (5 mL) togive a suspension. The suspension was filtered to give(1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (1.3 g, 64% yield): mp, 103–105° C.; ¹H NMR (CDCl₃) δ0.86–0.93 (m, 2H, CH₂), 1.08–1.12 (m, 2H, CH₂), 1.44 (t, J=7 Hz, 3H,CH₃), 1.64–1.73 (m, 1H, CH), 2.11–2.32 (m, 2H, CH₂), 3.37 (dd, J=4, 9Hz, 1H, OH), 3.50–3.59 (m, 1H, CHH), 3.74–3.79 (m, 2H, NCHH, CHH), 3.80(s, 3H, CH₃), 4.06 (q, J=7 Hz, 2H, CH₂), 4.16 (d, J=18 Hz, 1H, NCHH),6.65 (dd, J=4, 11 Hz, 1H, NCH), 6.83–6.99 (m, 4H, Ar), 7.44 (t, J=8 Hz,1H, Ar), 8.45 (d, J=8Hz, 1H, Ar), 10.52 (s, 1H, NH); ¹³C NMR (CDCl₃) δ8.35, 14.77, 16.22, 33.85, 46.23, 50.52, 55.98, 58.59, 64.55, 111.36,112.99, 116.77, 116.99, 117.83, 119.77, 130.73, 133.37, 138.05, 141.49,148.62, 149.25, 170.33, 172.76; Anal Calcd for C₂₄H₂₈N₂O₅: C, 67.91; H,6.65; N, 6.60. Found: C, 67.92; H, 6.67; N, 6.37.

5.2. Example 2(3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate

A solution of(3R)-N-[3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propyl](tert-butoxy)carbonylamino(tert-butoxy)formate (4.1 g, 7.2 mmol), cyclopropanecarbonyl chloride(0.80 mL, 8.8 mmol) and triethylamine (1.3 mL, 9.3 mmol) in THF (20 mL)was heated at reflux for 2 hrs. The solution was extracted with ethylacetate (100 mL) and sodium hydrogen carbonate (sat, 50 mL). The organiclayer was washed with sodium hydrogen carbonate (sat, 50 mL), brine (50mL), and dried over MgSO₄. The solvent was removed in vacuo to give(3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate as a white solid (4.4 g, 95% yield): mp, 153–155°C.; ¹H NMR (CDCl₃) δ 0.84–0.92 (m, 2H, CH₂), 1.06–1.13 (m, 2H, CH₂),1.42 (s, 9H, 3CH₃), 1.43 (t, J=7 Hz, 3H, CH₃), 1.50 (s, 9H, 3CH₃),1.65–1.73 (m, 1H, CH), 2.38–2.48 (m, 2H, CH₂), 3.61–3.73 (m, 2H, CH₂),3.85 (s, 3H, CH₃), 4.03 (d, J=18 Hz, 1H, NCHH), 4.04 (q, J=7 Hz, 2H,CH₂),4.33 (d, J=18 Hz, 1H, NCHH), 5.47 (t, J=7 Hz, 1H, NCH), 6.81–7.00(m, 4H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.61(s, 1H, NH); ¹³C NMR (CDCl₃) δ8.21, 14.76, 16.16, 27.58, 28.03, 29.14,46.21, 47.93, 52.21, 55.96, 58.45, 64.54, 82.57, 85.01, 111.45, 112.58,116.73, 117.54, 117.67, 119.37, 131.36, 133.08, 138.02, 141.39, 148.59,149.12, 152.21, 154.61, 169.50, 172.70; Anal Calcd for C₃₄H₄₅N₃O₉: C,63.83; H, 7.09; N, 6.57. Found: C, 63.84; H, 7.03; N, 6.44.

5.3. Example 3 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

A solution of(3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate (4.1 g, 6.4 mmol) in methylene chloride (20 mL) andtrifluoromethylacetic acid (9 mL)was stirred at room temperature for 1.5hrs. The solvent was removed in vacuo to give a yellow oil. The oil wasextracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (sat,50 mL). The organic layer was washed with brine (50 mL), and dried overMgSO₄. The solvent was removed in vacuo to give an oil. The oil wasslurried in ether (15 mL) to give a suspension. The suspension wasfiltered to give (3R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas white solid (2.1 g, 75% yield): mp, 136–138° C.; ¹H NMR (CDCl₃) δ0.84–0.91 (m, 2H, CH₂), 1.06–1.14 (m, 2H, CH₂), 1.43 (t, J=7 Hz, 3H,CH₃), 1.64–1.71 (m, 1H, CH), 2.23–2.45 (m, 2H, CH₂), 2.99 (t, J=7 Hz,2H, CH₂), 3.85 (s, 3H, CH₃), 3.95 (d, J=16 Hz, 1H, NCHH), 4.06 (q, J=7Hz, 2H, CH₂), 4.26 (d, J=16 Hz, 1H, NCHH), 5.57 (dd, J=6, 10 Hz, 1H,NCH), 6.81–6.99 (m, 4H, Ar), 7.41 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8Hz,1H, Ar), 10.57 (s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.27, 14.77, 16.19, 28.83,45.79, 50.40, 51.49, 55.96, 64.57, 111.44, 112.84, 116.73, 117.39,117.73, 119.52, 131.27, 133.13, 137.99, 141.36, 148.62, 149.18, 169.55,172.72; Anal Calcd for C₂₄H₂₉N₃O₅: C, 65.59; H, 6.65; N, 9.56. Found: C,65.30; H, 6.63; N, 9.21.

5.4. Example 4 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of (1R)-cyclopropanecarboxylic acid{2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(0.45 g, 1.1 mmol) and triethylamine (0.3 mL, 2 mmol) in methylenechloride (10 mL) was added methane sulfonyl chloride (0.10 mL, 1.3 mmol)at 0° C. After 3 hrs, the mixture was extracted with methylene chloride(20 mL) and water (20 mL). The organic layer was washed with HCl (1N, 20mL), sodium hydrogen carbonate (sat 20 mL), brine (20 mL), and driedover MgSO₄. The solvent was removed in vacuo to give a solid, which waspurified with chromatography (Silca Gel) to give(1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (320 mg, 58% yield): mp, 93–95° C.; ¹H NMR (CDCl₃) δ0.89–0.93 (m, 2H, CH₂), 1.08–1.10 (m, 2H, CH₂), 1.42 (t, J=7 Hz, 3H,CH₃), 1.65–1.72 (m, 1H, CH), 2.27–2.32 (m, 2H, CH₂), 2.94 (s, 3H, CH₃),2.97–3.06 (m, 1H, CHH), 3.85 (s, 3H, CH₃), 3.50 (d, J=17 Hz, 1H, NCHH),4.04 (q, J=7 Hz, 2H, CH₂), 4.18 (d, J=17 Hz, 1H, NCHH), 5.51 (dd, J=6, 9Hz, 1H, NCH), 5.60–5.62 (m, 1H, NH), 6.81–6.99 (m, 4H, Ar), 7.42 (t, J=8Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); ¹³C NMR(CDCl₃) δ 8.35, 14.76, 16.19, 32.26, 40.24, 40.65, 46.05, 51.12,55.98,64.63, 111.50, 112.83, 116.86, 116.94, 117.84, 119.64, 130.31,133.43, 138.02, 141.44, 148.72, 149.41, 170.07, 172.72; Anal Calcd forC₂₅H₃₁N₃O₆S+0.35 H₂O: C, 59.12; H, 6.29; N, 8.27, H₂O 1.26. Found: C,59.42; H, 6.16; N, 8.05, H₂O 1.24.

5.5. Example 5 (1R)-Cyclopropanecarboxylic acid{2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of triphenyl phosphine (1.4 g, 5.2 mmol),(1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(1.5 g, 3.4 mmol) and tert-butyl[(tert-butoxy)carbonylamino]formate (2.3g, 10 mmol) in THF (15 mL) was added a solution of DIAD (1 mL, 5.1 mmol)in THF (10 mL) at room temperature. After 1.5 hrs, the residue waspurified with chromatography (Silca Gel) to give (3R)-tert-butyl(N-{(3R)-3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}(tert-butoxy)carbonylamino)formateas an oil(2.4 g). The oil in trifluoroacetic acid (5 mL) and methylenechloride (5 mL) was stirred at room temperature for 1 hr. The solventwas removed in vacuo to give an oil. The oil was stirred in ether (10mL) to give a suspension. The suspension was filtered to give(1R)-cyclopropanecarboxylic acid{2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideCF₃COOH salt as a white solid (1.1 g, 57% yield). mp, 169–171° C.; ¹HNMR (DMSO-d₆) δ 0.89–0.94 (m, 4H, 2CH₂), 1.31 (t, J=7 Hz, 3H, CH₃),1.72–1.79 (m, 1H, CH), 2.31–2.41 (m, 2H, CH₂), 2.80–2.82 (m, 2H, CH₂),3.74 (s, 3H, CH₃), 3.99–4.09 (m, 3H, CH₂, NCHH), 4.53 (d, J=18 Hz, 1H,NCHH), 5.35 (dd, J=6, 9 Hz, 1H, NCH), 6.91–6.99 (m, 3H, Ar), 7.19 (d,J=8 Hz, 1H, Ar) 7.51 (t, J=8 Hz, 1H, Ar), 7.80 (br. s, 3H, NH₃), 8.23(d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 7.78, 14.70,15.48, 29.20, 36.69, 45.99, 51.58, 55.49, 63.84, 112.01, 112.35, 116.91,117.19, 117.59, 119.59, 130.87, 132.89, 136.98, 142.32, 148.05, 148.74,168.55, 171.69; Anal Calcd for C₂₄H₂₉N₃O₄+1.2 CF₃COOH: C, 56.59; H,5.43; N, 7.50. Found: C, 56.65; H, 5.39; N, 7.26.

5.6. Example 6 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-ureido-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of (1R)-cyclopropanecarboxylic acid{2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideCF₃COOH salt (0.40 g, 0.74 mmol) in HCl (10 mL, 0.5 M) was added asolution of potassium cyanate (240 mg, 3 mmol) in water (3 mL). Thesuspension was heated at 50° C. overnight. The mixture was extractedwith ethyl acetate (50 mL) and water (20 mL). The organic layer waswashed with HCl (1N, 50 mL), brine (50 mL), and dried over MgSO₄. Thesolvent was removed in vacuo to give a solid, which was purified withprep HPLC to give (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-ureido-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (220 mg, 65% yield): mp, 162–164° C.; ¹H NMR (DMSO-d₆)δ 0.88 (d, J=6 Hz, 4H, 2CH₂), 1.31 (t, J=7 Hz, 3H, CH₃), 1.72–1.79 (m,1H, CH), 2.11–2.23 (m, 2H, CH₂), 2.90–2.99 (m, 2H, CH₂), 3.73 (s, 3H,CH₃), 3.93–4.13 (m, 3H, NCHH, CH₂), 4.57 (d, J=17 Hz, 1H, NCHH), 5.28(t, J=9 Hz, 1H, NH), 5.48 (s, 2H, NH₂), 6.01 (t, J=5 Hz, 1H, NCH),6.88–6.94 (m, 3H, Ar), 7.17 (d, J=8 Hz, 1H, Ar), 7.48 (t, J=8 Hz, 1H,Ar), 8.22 (d, J=8 Hz, 1H, Ar), 10.59 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ7.75, 14.72, 15.48, 31.97, 36.81, 45.89, 51.74, 55.45, 63.78,111.97,112.34, 116.79, 117.33, 117.52, 119.67, 131.93, 132.68, 136.95,142.29, 147.96, 148.46, 159.69, 168.27, 171.68; Anal Calcd forC₂₅H₃₀N₄O₅+0.6 H₂O: C, 62.91; H, 6.59; N, 11.74, H₂O 2.26. Found: C,62.60; H, 6.32; N, 11.56, H₂O 1.20.

5.7. Example 7 (1R)-Cyclopropanecarboxylic acid{2-[3-dimethylamino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amidehydrochloride

A mixture of (1R)-cyclopropanecarboxylic acid{2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideCF₃COOH salt (0.56 g, 1.0 mmol), Pd/C (150 mg) and formaldehyde (400 mg,5 mmol) in methanol (40 mL) was shaken under hydrogen (50 psi)overnight. The suspension was filtered thru a pad of Celite. The solventwas removed in vacuo. The residue was extracted with methylene chloride(50 mL) and sodium hydrogen carbonate (sat, 50 mL). The organic layerwas washed with brine (50 mL), and dried over MgSO₄. The solvent wasremoved in vacuo to give a solid, which was purified with prep HPLC togive (1R)-cyclopropanecarboxylic acid{2-[3-dimethylamino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amidehydrochloride as a white solid (220 mg, 44% yield): mp, 119–121° C.; ¹HNMR (DMSO-d₆) δ 0.88 (d, J=6 Hz, 4H, 2CH₂), 1.32 (t, J=7 Hz, 3H, CH₃),1.73–1.79 (m, 1H, CH), 2.42–2.59 (m, 2H, CH₂), 2.76 (s, 3H, CH₃), 2.78(s, 3H, CH₃), 3.02–3.10 (m, 2H, CH₂), 3.74 (s, 3H, CH₃), 3.99–4.06 (m,3H, NCHH, CH₂), 4.59 (d, J=17 Hz, 1H, NCHH), 5.32 (dd, J=5, 10 Hz, 1H,NH), 6.96 (brs, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.51 (t, J=8 Hz, 1H,Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.46 (brs, 1H, HCl) 10.54 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 7.79, 14.71, 15.47, 25.86, 42.00, 42.05, 45.72,51.54, 54.07, 55.49, 63.89, 111.96, 122.29, 116.88, 117.22, 117.61,119.75, 130.64, 132.85, 136.99, 142.37, 148.07, 148.75, 168.42, 171.72;Anal Calcd for C₂₆H₃₄N₃O₄Cl+1 H₂O: C, 61.71; H, 7.17; N, 8.30, Cl, 7.01,H₂O 3.56. Found: C, 61.85; H, 7.26; N, 7.99, Cl, 7.51, H₂O 3.36.

5.8. Example 8 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of triphenyl phosphine (0.63 g, 2.4 mmol) in THF (10 mL)was added DIAD (0.47 mL, 2.4 mmol) at 0° C. After 10 min,(1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(0.93 mL, 2.2 mmol) was added as solid. After 5 min, sodiumthiomethoxide (180 mg, 2.6 mmol) was added. After 20 min, the cold bathwas removed and the mixture was stirred at room temperature for 1.5 hrs.To the mixture was added water (15 mL), methanol (15 mL), and oxone (5.4g, 8.8 mmol) and kept for 16 h. The mixture was extracted with methylenechloride (100 mL) and water (50 mL). The organic layer was dried overMgSO₄. The solvent was removed in vacuo to give a solid. The solid waspurified with prep HPLC to give (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (50 mg, 5% yield): mp, 148–150° C.; ¹H NMR (CDCl₃) δ0.89–0.94 (m, 2H, CH₂), 1.10–1.13 (m, 2H, CH₂), 1.46 (t, J=7 Hz, 3H,CH₃), 1.65–1.73 (m, 1H, CH), 2.60–2.69 (m, 2H, CH₂), 2.96 (s, 3H, CH₃),3.02–3.22 (m, 2H, CH₂), 3.87 (s, 3H, CH₃), 3.99 (d, J=17 Hz, 1H, NCHH),4.07 (q, J=7 Hz, 2H, CH₂), 4.30 (d, J=17 Hz, 1H, NCHH), 5.48 (t, J=8 Hz,1H, NCH), 6.84–7.02 (m, 4H, Ar), 7.46 (t, J=8 Hz, 1H, Ar), 8.45 (d, J=8Hz, 1H, Ar), 10.49 (s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.30, 14.75, 16.19,23.78, 41.24, 45.95, 51.99, 53.01, 56.00, 64.65, 111.60, 112.37, 116.88,117.00, 117.89, 119.46, 129.82, 133.52, 138.09, 141.29, 148.87, 149.55,169.79, 172.66; Anal Calcd for C₂₅H₃₀N₂O₆S₁: C, 61.71; H, 6.21; N, 5.76.Found: C, 61.33; H, 6.19; N, 5.59.

5.9. Example 9 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

A solution of(1R)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid (300 mg, 0.68 mmol) and CDI (130 mg, 0.81 mmol) in THF (3 mL) wasstirred at room temperature for 2 hrs. To the mixture was addedhydroxylamine HCl (69 mg, 1 mmol) and kept for overnight. Water (20 mL)was added to the mixture. The suspension was filtered to give(1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (220 mg, 71% yield): mp, 160–162° C.; ¹H NMR (DMSO-d₆)δ 0.88–0.92 (m, 4H, 2CH₂), 1.31 (t, J=7 Hz, 3H, CH₃), 1.72–1.81 (m, 1H,CH), 2.85 (d, J=8 Hz, 2H, CH₂), 3.73 (s, 3H, CH₃), 4.01 (q, J=7 Hz, 2H,CH₂), 4.16 (d, J=18 Hz, 1H, NCHH), 4.57 (d, J=18 Hz, 1H, NCHH), 5.68 (t,J=8 Hz, 1H, NCH), 6.86–6.95 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar) 7.49(t, J=8 Hz, 1H, Ar), 8.22 (d, J=8 Hz, 1H, Ar), 8.83 (s, 1H, OH), 10.56(s, 1H, NH), 10.58 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 7.77, 14.72, 15.47,35.03, 46.44, 51.33, 55.48, 63.81, 111.93, 112.16, 116.81, 117.38,117.51, 119.37, 131.45, 132.74, 136.96, 142.21, 147.94, 148.55, 165.93,167.97, 171.11; Anal Calcd for C₂₄H₂₇N₃O₆: C, 63.57; H, 6.00; N, 9.27.Found: C, 63.24; H, 5.69; N, 8.91.

5.10. Example 10 (1R)-Cyclopropanecarboxylic acid{2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

A solution of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideand acetic anhydride (0.09 mL, 1 mmol) in acetonitrile/methylenechloride (6 mL each) was stirred at room temperature for 21 hrs. Ether(10 mL) and hexane (10 mL) was added to give a suspension. Thesuspension was filtered to give (1R)-cyclopropanecarboxylic acid{2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (270 mg, 63% yield): mp, 140–142° C.; ¹H NMR (DMSO-d₆)δ 0.88–0.92 (m, 4H, 2CH₂), 1.30 (t, J=7 Hz, 3H, CH₃), 1.75–1.81 (m, 1H,CH), 2.09 (s, 3H, CH₃), 3.02–3.07 (m, 2H, CH₂), 3.73 (s, 3H, CH₃), 4.01(q, J=7 Hz, 2H, CH₂), 4.18 (d, J=18 Hz, 1H, NCHH), 4.60 (d, J=18 Hz, 1H,NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86–6.95 (m, 3H, Ar), 7.18 (d, J=8Hz, 1H, Ar) 7.49 (t, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54(s, 1H, NH), 11.86 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 7.79, 14.70, 15.46,17.95, 17.95, 34.55, 46.53, 51.06, 55.44, 63.76, 111.87, 111.99, 116.77,117.29, 117.47, 119.23, 131.17, 132.74, 136.94, 142.25, 147.92, 148.52,166.48, 168.02, 168.32, 171.70; Anal Calcd for C₂₆H₂₉N₃O₇+0.1 H₂O: C,62.79; H, 5.92; N, 8.45, H₂O, 0.36. Found: C, 62.44; H, 5.82; N, 8.37,H₂O, 0.30.

5.11. Example 11 (3R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfinyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(5.7 g, 13 mmol), triphenyl phosphine (7.1 g, 2.4 mmol) and thioaceticacid (2.2 mL, 31 mmol) in THF (50 mL) was added a solution of DIAD (5.5mL, 28 mmol) in THF (50 mL) at room temperature. After 4 hrs, methanol(5 mL) was added to the solution. The solvent was removed in vacuo. Theresidue was purified with Chromatography to give (3R)-thioacetic acidS-[3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propyl]ester(5.1 g, 79% yield). To a solution of (3R)-thioacetic acidS-[3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propyl]ester(5.0 g, 10 mmol) and methyl iodide (0.8 mL, 13 mmol) in methanol (40 mL)was added a solution of sodium hydroxide (5N, 4.2 mL, 21 mmol) at roomtemperature. After 2 hrs, to the mixture was added water (40 mL),methylene chloride (20 mL), and oxone (18 g, 29 mmol) and kept for 1.5hrs. The mixture was extracted with methylene chloride (100 mL) andwater (50 mL). The organic layer was washed with Na₂S₂O₃ (10% 50 mL),brine (50 mL) and dried over MgSO₄. The solvent was removed in vacuo.The residue was purified with chromatography (Silica Gel) to give(3R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfinyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (320 mg, 6% yield): mp, 122–125° C.; ¹H NMR (CDCl₃) δ0.86–0.93 (m, 2H, CH₂), 1.08–1.14 (m, 2H, CH₂), 1.45 (t, J=7 Hz, 3H,CH₃), 1.63–1.72 (m, 1H, CH), 2.58 and 2.59 (2s, 3H, CH₃), 2.60–2.82 (m,4H, CH₂CH₂), 3.86 (s, 3H, CH₃), 3.97 (d, J=17 Hz, 1H, NCHH), 4.06 (q,J=7 Hz, 2H, CH₂), 4.31 and 4.35 (2 sets of d, J=17 Hz, 1H, NCHH),5.50–5.59 (m, 1H, NCH), 6.84–7.02 (m, 4H, Ar), 7.41–7.48 (m, 1H, Ar),8.43 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.28,14.76, 16.18, 24.28, 24.76, 38.95, 45.71, 45.89, 51.22, 51.42, 53.07,53.63, 55.99, 64.64, 111.54, 112.49, 116.89, 117.19, 117.80, 119.54,130.38, 130.48, 133.37, 138.04, 141.36, 148.77, 149.40, 169.79, 169.82,172.66; Anal Calcd for C₂₅H₃₀N₂O₅S+0.8 H₂O: C, 61.93; H, 6.57; N, 5.78;H₂O, 2.97. Found: C, 61.63; H, 6.62; N, 5.61; H₂O, 2.19.

5.12. Example 12(3R)-3-[4-Chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid

To a solution of(3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid methyl ester (3.0 g, 6.2 mmol) in THF (60 ml) was added NaOH (10N,1.2 ml, 12 mmol). The mixture was stirred at room temperature overnight.To it was added water (50 ml). The mixture was extracted with EtOAc (50ml×2). The aqueous layer was acidified by conc. HCl until pH=6. Theresulted cloudy mixture was extracted with EtOAc (50 ml×2). The organicelayer was washed with water (30 ml×2), brine (30 ml), dried over Na₂SO₄,filtered and concentrated in vacuo to give(3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid as a white solid (2.8 g, 99%): mp, 118–120° C.; ¹H NMR (CDCl₃) δ0.86–0.91 (m, 2H, c-CH₂), 1.05–1.11 (m, 2H, c-CH₂), 1.45 (t, J=7.0 Hz,3H, OCH₂CH₃), 1.65–1.70 (m, 1H, c-CH), 3.13 (dd, J=6, 15 Hz, 1H, CHH),3.23 (dd, J=10, 15 Hz, 1H, CHH), 3.86 (s, 3H, OCH₃), 4.00–4.11(m, 3H,NCHH+OCH₂CH₃), 4.32 (d, J=18 Hz, 1H, NCHH), 5.80–5.86 (m, 1H, CHN),6.83–6.92 (m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H,Ar), 10.39 (s, 1H, NHCO). ¹³CNMR (CDCl₃): δ 8.4, 8.5, 14.7, 16.1, 36.7,45.9, 51.8, 55.9, 64.6, 111.5, 112.4, 118.9, 119.0, 1198, 121.9, 130.1,132.9, 136.7, 139.0, 148.7, 149.5, 168.7, 172.8, 173.8; Anal Calcd forC₂₄H₂₅ClN₂O₆+0.37 H₂O: C, 60.11; H, 5.41; N, 5.84. Found: C, 60.11; H,5.25; N, 5.64, H₂O, 1.40.

5.13. Example 13(3R)-3-[4-Chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid methyl ester

To a solution of (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid methyl ester (3.0 g, 8.7 mmol) in DMF (25 ml) was added2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acidmethyl (2.2 g, 8.6 mmol) and triethyl amine (2.4 ml, 17 mmol). Themixture was heated at 90° C. overnight. The solvent was removed invacuo. The resulted oil was extracted with ethyl acetate (50 ml) andwater (30 ml). The organic layer was washed with water (30 ml×2), brine(30 ml) and dried over magnesium sulfate. The solvent was removed invacuo and the resulted oil was purified by silica gel column to give(3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid methyl ester as a white solid (3.5 mg, 83%): mp, 158–160° C.; ¹HNMR (CDCl₃) δ 0.86–0.93 (m, 2H, c-CH₂), 1.07–1.13 (m, 2H, c-CH₂), 1.46(t, J=7.0 Hz, 3H, OCH₂CH₃), 1.64–1.71 (m, 1H, c-CH), 3.10(dd, J=6, 15Hz, 1H, CHH), 3.24 (dd, J=10, 15 Hz, 1H, CHH), 3.67 (s, 3H, COOCH₃),3.86 (s, 3H, OCH₃), 4.03 (d, J=18 Hz, 1H, NCHH), 4.10 (t, J=7.0 Hz, 2H,OCH₂CH₃), 4.31 (d, J=18 Hz, 1H, NCHH), 5.82–5.88 (m, 1H, CHN), 6.84–6.93(m, 3H, Ar), 7.37 (d, J=8 Hz, 1H, Ar), 8.44 (d, J=8 Hz, 1H, Ar), 10.47(s, 1H, NHCO). ¹³CNMR (CDCl₃): δ 8.4, 14.7, 16.1, 36.7, 45.9, 51.8,52.1, 55.9, 64.6, 111.5, 118.9, 119.0, 119.6, 121.8, 130.2, 132.8,136.7, 139.0, 148.7, 149.3, 168.5, 170.6, 172.7, 184.3; Anal Calcd forC₂₅H₂₇ClN₂O₆: C, 61.66; H, 5.59; N, 5.75. Found: C, 61.32; H, 5.49; N,5.70.

5.14. Example 14 (1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of(3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid (0.62 g, 1.3 mmol) in THF (5 ml) was added carbonyldiimidazole (0.3g, 2 mmol) at room temperature. The solution was stirred for 2 hrs atroom temperature. To the mixture was added NH₄OH (13.8 N, 0.3 ml, 3.9mmol). The resulting mixture was stirred at room temperature for 4 hrs.Water (20 ml) was added to the reaction mixture. THF was removed invacuo and to the resulting mixture was added ethyl acetate (30 ml). Themixture was washed with saturated sodium bicarbonate solution (3×20 ml),water (20 ml) and brine (20 ml). The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo. The resulting oilwas stirred with ether (5 ml) for 2 hrs and filtered to give(1R)-cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas white solid (0.5 g, 82%): mp 201–203° C.; ¹HNMR (CDCl₃): δ 0.88–0.91(m, 2H, c-CH₂), 1.08–1.11(m, 2H, c-CH₂), 1.45 (t, J=7.5 Hz, 3H,OCH₂CH₃), 1.65–1.68 (m, 1H, c-CH), 2.98 (dd, J=5, 16 Hz, 1H, CHH), 3.36(dd, J=5, 16 Hz, 1H, CHH), 3.86 (s, 3H, OCH₃), 4.08 (q, J=7.5 Hz, 2H,OCH₂CH₃), 4.13 (d, J=17 Hz, 1H, NCHH), 4.35 (d, J=17 Hz, 1H, NCHH), 5.42(broad s, 1H), 5.58–5.64 (m, 1H, CHN), 6.00 (broad s, 1H), 6.83–6.95 (m,3H, Ar), 7.36 (d, J=9 Hz, 1H, Ar), 8.43 (d, J=9 Hz, 1H, Ar), 10.41 (s,1H); ¹³C NMR (CDCl₃): 8.4, 14.7, 16.1, 38.6, 48.6, 46.7, 53.2, 53.4,56.0, 64.5, 65.8, 112.2, 119.0, 119.1, 119.5, 121.8, 130.6, 132.8,136.6, 139.1, 148.7, 149.4, 169.0, 171.8, 172.6; Anal. Calcd. forC₂₄H₂₆ClN₃O₅: C, 61.08; H, 5.55; N, 8.90. Found: C, 60.89; H, 5.42; N,8.51.

5.15. Example 15 (1R)-Cyclopropanecarboxylic acid{7-chloro-2-[2-dimethylcarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of(3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid (0.62 g, 1.3 mmol) in tetrahydrofurane (5 ml) was addedcarbonyldiimidazole (0.3 g, 2 mmol) at room temperature. The solutionwas stirred for 2 hours at room temperature. To the mixture was addedTHF solution of dimethylamine (2 M, 1.3 ml, 2.6 mmol). The resultedmixture was stirred at room temperature for 4 hrs. Water (20 ml) wasadded to the reaction mixture. THF was removed in vacuo and to theresulted mixture was added ethyl acetate (30 ml). The mixture was washedwith saturated sodium bicarbonate solution (3×20 ml), water (20 ml) andbrine (20 ml). The organic layer was dried over magnesium sulfate,filtered and concentrated in vacuo. The resulted oil was stirred withether (5 ml) for 2 hrs and filtered to give (1R)-cyclopropanecarboxylicacid{7-chloro-2-[2-dimethylcarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas white solid (0.5 g, 77%): mp 163–165° C.; ¹HNMR (CDCl₃): δ 0.86–0.89(m, 2H, c-CH₂), 1.08–1.11(m, 2H, c-CH₂), 1.46 (t, J=7.5 Hz, 3H,OCH₂CH₃), 1.65–1.68 (m, 1H, c-CH), 2.93 (s, 3H, NCH₃), 3.04 (dd, J=5, 16Hz, 1H, CHH), 3.12 (s, 3H, NCH₃), 3.56 (dd, J=5, 16 Hz, 1H, CHH), 3.86(s, 3H, OCH₃), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.25 (d, J=17 Hz, 1H,NCHH), 4.60 (d, J=17 Hz, 1H, NCHH), 5.58–5.64 (m, 1H, CHN), 6.83–6.97(m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H, Ar), 10.51(s, 1H, NH); ¹³C NMR (CDCl₃): 8.9, 15.4, 16.8, 36.2, 36.6, 38.0, 48.6,54.3, 56.6, 65.2, 112.1, 113.1, 119.8, 120.0, 120.1, 122.3, 132.2,133.2, 137.3, 139.9, 149.2, 149.8, 169.4, 170.1, 173.2; Anal. Calcd. forC₂₆H₃₀ClN₃O₅: C, 62.46; H, 6.05; N, 8.40. Found: C, 62.43; H, 5.42; N,8.51.

5.16. Example 16 (1R)-Cyclopropanecarboxylic acid{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of(3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionicacid (1.3 g, 2.8 mmol) in tetrahydrofurane (10 ml) was addedcarbonyldiimidazole (0.7 g, 4.2 mmol) at room temperature. The solutionwas stirred for 2 hours at room temperature. To the mixture was addedhydroxylamine HCl salt (0.4 g, 5.6 mmol). The resulted mixture wasstirred at room temperature for 4 hours. Water (20 ml) was added to thereaction mixture. THF was removed in vacuo and the resulted mixture wasadded ethyl acetate (30 ml). The mixture was washed with saturatedsodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml).The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The resulted oil was stirred with ether (5 ml)for 2 hours and filtered to give (1R)-cyclopropanecarboxylic acid{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas white solid (1.2 g, 86%): mp 142–144° C.; ¹HNMR (DMSO-d₆): δ0.87–0.89 (m, 4H, c-CH₂), 1.28–1.33 (t, J=7.5 Hz, 3H, OCH₂CH₃),1.78–1.83 (m, 1H, c-CH), 2.85–2.91 (m, 2H, CH₂CO), 3.73 (s, 3H), 4.00(t, J=7.5 Hz, 2H, OCH₂CH₃), 4.11 (d, J=17 Hz, 1H, NCHH), 4.60 (d, J=17Hz, 1H, NCHH), 5.53–5.69 (m, 1H, CHN), 6.92–6.94 (m, 3H, Ar), 7.58 (d,J=10 Hz, 1H, Ar), 8.26 (d, J=10 Hz, 1H, Ar), 8.84 (s, 1H), 10.46 (s,1H), 10.57 (s, 1H); ¹³C NMR (DMSO-d₆): δ 8.4, 8.5, 15.2, 15.9, 35.4,46.2, 52.2, 55.9, 64.3, 74.6, 112.4, 112.7, 119.7, 119.8, 121.5, 131.7,132.9, 136.4, 140.2, 148.4, 149.1, 166.3, 167.6, 172.4; Anal. Calcd. forC₂₆H₂₈ClN₃O₇+0.5 H₂O: C, 58.01; H, 5.48; N, 8.46. Found: C, 57.97; H,5.29; N, 8.53, H₂O, 1.5.

5.17. Example 17 (1R)-Cyclopropanecarboxylic acid{2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl)-amide

To the solution of cyclopropanecarboxylic acid{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(0.45 g, 92 mmol) in CH₃CN (50 ml) was added acetic anhydride (0.1 ml,92 mmol) at room temperature. The mixture was stirred overnight. Thesolvent was removed in vacuo and the resulted solid was stirred withether (10 ml) for 2 hrs. The suspension was filtered and the solid wasdried in oven to give (1R)-cyclopropanecarboxylic acid{2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(0.4 g, 80%): mp 139–141° C.; ¹HNMR (CDCl₃): δ 0.85–0.92 (m, 2H, c-CH₂),1.05–1.11 (m, 2H, c-CH₂), 1.43 (t, J=7.5 Hz, 3H, OCH₂CH₃), 1.62–1.68 (m,1H, c-CH), 2.12 (s, 3H, CH₃), 3.02 (dd, J=5, 16 Hz, 1H, CHH), 3.50 (dd,J=5, 16 Hz, 1H, CHH), 3.85 (s, 3H, OCH₃), 4.08 (q, J=7.5 Hz, 2H,OCH2CH3), 4.12 (d, J=17 Hz, 1H, CHH), 4.38 (d, J=17 Hz, 1H, CHH),5.61–5.65 (m, 1H, CHN), 6.81–6.94 (m, 3H, Ar), 7.31 (d, J=10 Hz, 1H,Ar), 8.38 (d, J=10 Hz, 1H, Ar), 10.41 (s, 1H); ¹³C NMR (CDCl₃): δ 9.0,9.1, 15.3, 16.7, 18.7, 36.8, 48.2, 54.4, 56.5, 65.2, 112.2, 112.8,119.7, 119.8, 120.2, 122.4, 131.1, 133.5, 137.2, 139.8, 149.3, 150.1,167.0, 169.0, 170.0, 173.5; Anal. Calcd. for C₂₆H₂₈ClN₃O₇: C, 58.92; H,5.33; N, 7.93. Found: C, 58.58; H, 5.00; N, 7.76.

5.18. Example 18 (1S)-Cyclopropanecarboxylic acid{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.4 g,5.1 mmol) in DMF (20 ml) was added2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acidmethyl ester (1.6 g, 4.6 mmol) and triethyl amine (2.0 ml, 14 mmol). Themixture was heated at 90° C. overnight. The solvent was removed invacuo. The resulted oil was extracted with ethyl acetate (50 ml) andwater (30 ml). The organic layer was washed with water (30 ml×2), brine(30 ml) and dried over magnesium sulfate. The solvent was removed invacuo and the resulted oil was purified by silica gel column to give(1S)-cyclopropanecarboxylic acid{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (650 mg, 30%): mp, 197–199° C.; ¹H NMR (CDCl₃) δ0.89–0.93 (m, 2H, c-CH₂), 1.08–1.12 (m, 2H, c-CH₂), 1.44 (t, J=7.0 Hz,3H, OCH₂CH₃), 1.65–1.69 (m, 1H, c-CH), 2.97 (s, 3H, CH₃SO₂), 3.70 (dd,J=5, 15 Hz, 1H, CHH), 3.87(s, 3H, OCH₃), 4.05–4.23 (m, 4H,NCH+CH+OCH₂CH₃), 4.41 (d, J=17 Hz, 1H, CHH), 5.75–5.81 (m, 1H, CHN),6.86–6.96 (m, 3H, Ar), 7.39 (d, J=9.0 Hz, 1H, Ar), 8.45(d, J=9.0 Hz, 1H,Ar), 10.36 (s, 1H, NHCO). ¹³CNMR (CDCl₃): δ 8.5, 14.7, 16.2, 41.6, 46.9,51.3, 55.5, 56.0, 64.7, 111.7, 112.3, 118.6, 119.3, 119.7, 121.8, 129.1,133.2, 136.8, 139.0, 149.0, 149.9, 169.2, 172.6; Anal Calcd forC₂₄H₂₇ClN₂O₆S: C, 56.86; H, 5.37; N, 5.53. Found: C, 56.81; H, 5.26; N,5.56.

5.19. Example 19 (1S)-Cyclopropanecarboxylic acid{7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (0.35 g,1.2 mmol) in DMF (10 ml) was added2-bromomethyl-3-bromo-6-(cyclopropanecarbonyl-amino)-benzoic acid methylester (0.45 g, 1.1 mmol) and triethyl amine (0.5 ml, 3.3 mmol). Themixture was heated at 90° C. overnight. The solvent was removed invacuo. The resulted oil was extracted with ethyl acetate (50 ml) andwater (30 ml). The organic layer was washed with water (30 ml×2), brine(30 ml) and dried over magnesium sulfate. The solvent was removed invacuo and the resulted oil was purified by silica gel column to give(1S)-cyclopropanecarboxylic acid{7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (450 mg, 74%): mp, 219–221° C.; ¹H NMR (CDCl₃) δ0.89–0.93 (m, 2H, c-CH₂), 1.08–1.14 (m, 2H, c-CH₂), 1.47 (t, J=7.0 Hz,3H, OCH₂CH₃), 1.65–1.70 (m, 1H, c-CH), 2.98 (s, 3H, CH₃SO₂), 3.70 (dd,J=5, 15 Hz, 1H, CHH), 3.87(s, 3H, OCH₃), 4.06–4.14 (m, 3H,NCHH+OCH₂CH₃), 4.19 (dd, J=10, 15 Hz, 1H, CHH), 4.55 (d, J=17 Hz, 1H,CH), 5.75–5.81 (m, 1H, CHN), 6.86–6.96 (m, 3H, Ar), 7.53 (d, J=9 Hz, 1H,Ar), 8.40(d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO). ¹³CNMR (CDCl₃): δ9.1, 9.2, 15.4, 16.9, 42.2, 49.1, 52.0, 56.1, 56.7, 65.3, 110.1, 112.3,112.8, 119.5, 119.9, 120.7, 129.7, 136.8, 138.1, 142.0, 149.6, 150.5,170.0, 173.3; Anal Calcd for C₂₄H₂₇BrN₂O₆S: C, 52.27; H, 4.94; N, 5.08.Found: C, 52.57; H, 4.68; N, 4.95.

5.20. Example 20 Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

A solution of7-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one(1.0 g, 2.9 mmol) and cyclopropanecarbonyl chloride (0.32 mL, 3.5 mmol)in THF (10 mL) was heated to reflux for 40 min. The solvent was removedin vacuo. The residue was extracted with ethyl acetate (50 mL) andsodium hydrogen carbonate (sat, 50 mL). The organic layer was washedwith brine (50 mL) and dried over MgSO₄. The solvent was removed invacuo and the residue was purified with chromatography (Silica Gel) tocyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (900 mg, 76% yield): mp, 107–109° C.; ¹H NMR (CDCl₃) δ0.84–0.92 (m, 2H, CH₂), 0.99 (t, J=7 Hz, 3H, CH₃), 1.02–1.13 (, 2H,CH₂), 1.44 (t, J=7 Hz, 3H, CH₃), 1.64–1.73 (m, 1H, CH), 2.00–2.16 (m,2H, CH₂), 3.86 (s, 3H, CH₃), 4.00 (d, J=17 Hz, 1H, CHH), 4.09 (q, J=7Hz, 2H, CH₂), 4.27 (d, J=17 Hz, 1H, NCHH), 5.33 (dd, J=7, 9 Hz, 1H,NCH), 6.83–6.95 (m, 3H, Ar), 7.00 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8 Hz,1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.67 (s, 1H, NH); ¹³C NMR (CDCl₃) δ8.19, 11.18, 14.78, 16.18, 24.54, 45.64, 55.53, 55.97, 64.58, 111.46,112.91, 116.68, 117.67, 119.51, 131.96, 132.94, 138.02, 141.37, 148.54,149.04, 169.55, 172.70; Anal Calcd for C₂₄H₂₈N₂O₄: C, 70.57; H, 6.91; N,6.86. Found: C, 70.54; H, 6.91; N, 6.86.

5.21. Example 21 Cyclopropanecarboxylic acid{7-chloro-2-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To the DMF solution (20 ml) of3-Amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (1.55 g, 7 mmol) wasadded Et₃N (1.6 ml, 12 mmol) followed by2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acidmethyl ester (2.42 g, 7 mmol). The mixture was heated at 90° C. for 12hrs then cooled to room temperature. The mixture was extracted withEtOAc (50 ml) and water (50 ml). The organic layer was washed with water(50 ml) and brine (50 ml), dried over Na₂SO₄ and concentrated in vacuo.The resulted oil was purified by silica gel chromatography to givecyclopropanecarboxylic acid{7-chloro-2-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas white solid (2.4 g, 80%): mp 200–202° C.; ¹H NMR (CDCl₃) δ 0.90–0.94(m, 2H, c-CH₂), 1.09–1.14 (m, 2H, c-CH₂), 1.45 (t, J=7.0 Hz, 3H, CH₃),1.64–1.70(m, 1H, c-CH), 3.12–3.32(m, 2H, CH₂CN), 3.89(s, 3H), 3.99–4.12(m, 3H, OCH₂CH₃+CHNN), 4.37 (d, J=18 Hz, 1H. CHHN), 5.62–5.68 (m, 1H,NCH), 6.87–6.98 (m, 3H, Ar), 7.40 (d, J=9 Hz, 1H, Ar), 8.47 (t, J=9 Hz,1H, Ar), 10.34 (s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.5, 14.7, 16.2, 21.2,46.4, 51.8, 56.0, 64.7, 111.7, 112.2, 116.9, 118.4, 119.1, 119.8, 121.9,127.9, 133.3, 136.9, 138.9, 149.9, 150.0, 169.0, 172.7; Anal Calcd forC₂₄H₂₄ClN₃O₄: C, 63.50; H, 5.33; N, 9.26. Found: C, 63.43; H, 5.31; N,9.01

5.22. Example 22 Cyclopropanecarboxylic acid{2-[2-(3,5-dichloro-pyridin-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a mixture of2-(3,5-dichloro-pyridin-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)-ethanol (500mg, 1.5 mmol) and PPh₃ (0.60 g, 2.3 mmol), was added DIAD (0.44 mL, 2.2mmol) at 0° C. After 5 min, (PhO)₂PON₃ was added to the mixture at 0° C.The mixture was allowed to warm to room temperature overnight. To themixture was added PPh₃ (0.9 g, 3.5 mmol) and water (2 mL). The mixturewas heated to reflux for 6 hrs. The mixture was extracted with ether (25mL) and 1N HCl (2×25 mL). The aqueous layer was basified with 10 Nsodium hydroxide until pH=14. The aqueous layer was extracted withmethylene chloride (2×50 mL). The combined organic layer wasconcentrated to give an oil. A mixture of the resulted oil,2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester(100 mg, 0.64 mmol) and triethyl amine (0.1 mL, 0.7 mmol) in DMF (5 mL)was heated at 80° C. for 27 hrs. The solvent was removed in vacuo. Theresidue was extracted with ethyl acetate (50 mL) and water (50 mL). Theorganic layer was washed with water (50 mL) and brine (50 mL). Thesolvent was removed in vacuo. The residue was purified with PreparativeHPLC to give cyclopropanecarboxylic acid{2-[2-(3,5-dichloro-pyridin-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(130 mg, 16% yield): mp, 159–161° C.; ¹H NMR (CDCl₃) δ 0.81–0.91 (m, 2H,CH₂), 1.01–1.09 (m, 2H, CH₂), 1.45 (t, J=7 Hz, 3H, CH₃), 1.56–1.63 (m,1H, CH), 3.68 (dd, J=4, 13 Hz 1H, CHH), 3.79 (dd, J=11, 13 Hz, 1H, CHH),3.89 (s, 3H, CH₃), 3.91 (d, J=17 Hz, 1H, NCHH), 4.08 (q, J=7 Hz, 2H,CH₂), 4.56 (d, J=17 Hz, 1H, NCHH), 5.94 (dd, J=4, 11 Hz, 1H, NCH), 6.86(m, 4H, Ar), 7.41 (t, J=8 Hz, 1H, Ar), 8.40 (d, J=8 Hz, 1H, Ar), 8.43(s, 2H, pyr), 10.28 (s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.27, 14.76, 16.09,33.22, 46.71, 52.63, 56.00, 64.66, 111.44, 112.69, 116.62, 116.95,117.67, 119.52, 130.65, 133.11, 133.19, 137.96, 141.40, 142.89, 147.59,148.75, 149.52, 169.32, 172.75; Anal Calcd for C₂₈H₂₇N₃O₄Cl₂: C, 62.23;H, 5.04; N, 7.78. Found: C, 61.99; H, 5.09; N, 7.43.

5.23. Example 23 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

Step 1: To a solution of(1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-oxo-butyl]-carbamic acidtert-butyl ester (1 g, 3 mmol) in THF (10 mL) was added a solution ofmethyl lithium (4 mL, 3M, 12 mmol) at 0° C. To the mixture was addedmethanol (5 mL). The residue was extracted with ethyl acetate (50 mL)and NH₄Cl (sat, 25 mL). The organic layer was washed with brine (100 mL)and dried over MgSO₄. The solvent was removed in vacuo. The residue waspurified with preparative HPLC to give(R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamicacid tert-butyl ester (150 mg, 14% yield).

Step 2: To a solution of(1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamicacid tert-butyl ester (150 mg, 0.42 mmol) in methylene chloride (5 mL)was added a solution of HCl in dioxane (0.5 mL, 4N, 2 mmol). After 2hrs, the solvent was removed and the crude oil was used in the next stepwithout further purification. A mixture of the resulted oil,2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester(130 mg, 0.42 mmol) and triethyl amine (0.12 mL, 0.86 mmol) in DMF (3mL) was heated at 80° C. for 27 hrs. The solvent was removed in vacuo.The residue was extracted with ethyl acetate (50 mL) and 1N HCl (50 mL).The organic layer was washed with 1N HCl (50 mL), brine (50 mL), anddried over MgSO₄. The solvent was removed in vacuo. The residue waspurified with Preparative HPLC to give (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(100 mg, 51% yield): mp, 90–92° C.; ¹H NMR (CDCl₃) δ 0.85–0.93 (m, 2H,CH₂), 1.08–1.13 (m, 2H, CH₂), 1.25 (s, 3 H, CH₃), 1,34 (s, 3H,CH₃), 1.45(t, J=7 Hz, 3H, CH₃), 1.67–1.74 (m, 1H, CH), 2.18 (dd, J=4, 14 Hz 1H,CHH), 2.32 (dd, J=9, 14 Hz, 1H, CHH), 2.38 (s, 1H, OH), 3.86 (s, 3H,CH₃), 3.94 (d, J=17 Hz, 1H, NCHH), 4.07 (q, J=7 Hz, 2H, CH₂), 4.36 (d,J=17 Hz, 1H, NCHH), 5.70 (dd, J=4, 9 Hz, 1H, NCH), 6.82–6.99 (m, 4H,Ar), 7.41 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.58 (s, 1H,NH); ¹³C NMR (CDCl₃) δ 8.27, 14.78, 16.19, 29.98, 30.22, 43.95, 46.13,50.96, 55.98, 64.60, 70.02, 111.43, 112.90, 116.71, 117.51, 117.69,119.72, 132.48, 133.16, 137.99, 141.50, 148.50, 149.12, 169.63, 172.72;Anal Calcd for C₂₆H₃₂N₂O₅+1.1 H₂O: C, 66.11; H, 7.30; N, 5.93. Found: C,65.73; H, 6.90; N, 5.82.

5.24. Example 24 (1R)-Cyclopropanecarboxylic acid{2-[2-cyclopropanecarbonyloxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(500 mg, 1.1 mmol) in acetonitrile (5 mL) was added cyclopropanecarbonylchloride (0.15 mL, 1.7 mmol) at room temperature and kept for 24 hrs.The solution was extracted with ethyl acetate (50 mL) and sodiumhydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO₄.Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid{2-[2-cyclopropanecarbonyloxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(380 mg, 66% yield): mp, 130–132° C.; ¹H NMR (DMSO-d₆) δ 0.81–1.01 (2ms, 8H, 4CH₂), 1.31 (t, J=7 Hz, 3H, CH₃), 1.70–1.80 (m, 1H, CH),2.97–3.05 (m, 2H, CH₂), 3.73 (s, 3H, CH₃), 3.97–4.04 (m, 2H, CH₂), 4.17(d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.66 (t, J=8 Hz,1H, NCh), 6.87–6.94 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.49 (d, J=8Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H NH), 12.00 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 7.77, 8.92, 10.28, 14.69, 15.46, 34.61, 46.60,51.11, 55.48, 63.80, 111.94, 112.11, 116.81, 117.31, 117.49, 119.27,131.22, 132.77, 136.96, 142.25, 147.94, 148.57, 166.59, 168.85, 171.72,172.41; Anal Calcd for C₂₈H₃₁N₃O₇+0.7 H₂O: C, 62.96; H, 6.11; N, 7.87.Found: C, 62.64; H, 5.89; N, 7.78.

5.25 Example 25 (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-isobutyryloxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(500 mg, 1.1 mmol) in acetonitrile (5 mL) was added isobutyryl chloride(0.15 mL, 1.4 mmol) at room temperature and kept for 24 hrs. Thesolution was extracted with ethyl acetate (50 mL) and sodium hydrogencarbonate (50 mL, sat). The organic layer was dried over MgSO₄.Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-isobutyryloxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(380 mg, 66% yield): mp, 107–109° C.; ¹H NMR (DMSO-d₆) δ 0.86–0.89 (m,4H, 2CH₂), 1.10 (d, J=7 Hz, 6H, 2CH₃), 1.31 (t, J=7 Hz, 3H, CH₃),1.73–1.81 (m, 1H, CH), 2.62–2.73 (m, 1H, CH), 3.02–3.05 (m, 2H, CH₂),3.73 (s, 3H, CH₃), 3.96–4.05 (m, 2H, CH₂), 4.19 (d, J=18 Hz, 1H, NCHH),4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86–6.94 (m,3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50 (d, J=8 Hz, 1H, Ar), 8.23 (d,J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH), 11.86 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 7.76, 14.69, 15.46, 18.65, 31.27, 34.64, 46.59, 51.07, 55.47, 63.80,111.93, 112.09, 116.82, 117.32, 117.50, 119.27, 131.23, 132.77, 136.98,142.25, 147.95, 148.58, 166.61, 168.04, 171.72, 174.29; Anal Calcd forC₂₈H₃₃N₃O₇+0.11 H₂O: C, 63.99; H, 6.37; N, 8.00; H₂O, 0.38. Found: C,63.64; H, 6.37; N, 7.70; H₂O, 0.39.

5.26. Example 26 (1R)-Cyclopropanecarboxylic acid{2-[2-(2,2-dimethyl-propionyloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(180 mg, 0.4 mmol) in acetonitrile (2 mL) was added2,2-dimethyl-propionyl chloride (0.064 mL, 0.5 mmol) at room temperatureand kept for 24 hrs. The solution was extracted with ethyl acetate (15mL) and sodium hydrogen carbonate (15 mL, sat). The organic layer wasdried over MgSO₄. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid{2-[2-(2,2-dimethyl-propionyloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(90 mg, 42% yield): mp, 146–148° C.; ¹H NMR (DMSO-d₆) δ 0.87–0.89 (m,4H, 2CH₂), 1.19 (s, 9H, 3CH₃), 1.30 (t, J=7 Hz, 3H, CH₃), 1.76–1.82 (m,1H, CH), 3.04 (d, J=8 Hz, 2H, CH₂), 3.73 (s, 3H, CH₃), 3.97–4.05 (m, 2H,CH₂), 4.19 (d, J=18 Hz, 1H, NCHH), 4.58 (d, J=18 Hz, 1H, NCHH), 5.66 (t,J=8 Hz, 1H, NCH), 6.87–6.94 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50(d, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.82(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 7.77, 14.69, 15.46, 26.71, 34.63,37.63, 46.61, 51.03, 55.46, 63.78, 111.91, 112.07, 116.82, 117.32,117.51, 119.24, 131.24, 132.76, 136.96, 142.24, 147.92, 148.55, 166.66,168.00, 171.71, 175.41; Anal Calcd for C₂₉H₃₅N₃O₇: C, 64.79; H, 6.56; N,7.82. Found: C, 64.91; H, 6.50; N, 7.84.

5.27 Example 27 (1R)-Cyclopropanecarboxylic acid{2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(500 mg, 1.1 mmol) in acetonitrile (5 mL) was added 3,3-dimethyl-butyrylchloride (0.2 mL, 1.4 mmol) at room temperature and kept for 24 hrs. Thesolution was extracted with ethyl acetate (50 mL) and sodium hydrogencarbonate (50 mL, sat). The organic layer was dried over MgSO₄.Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid{2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(360 mg, 59% yield): mp, 118–120° C.; ¹H NMR (DMSO-d₆) δ 0.87–0.89 (m,4H, 2CH₂), 0.98 (s, 9H, 3CH₃), 1.31 (t, J=7 Hz, 3H, CH₃), 1.73–1.80 (m,1H, CH), 2.27 (s, 2H, CH₂), 3.03–3.06 (m, 2H, CH₂), 3.73 (s, 3H, CH₃),3.97–4.03 (m, 2H, CH₂), 4.18 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz,1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86–6.94 (m, 3H, Ar), 7.18 (d,J=8 Hz, 1H, Ar), 7.49 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=8 Hz, 1H, Ar),10.55 (s, 1H, NH), 11.82 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 7.75, 14.70,15.46, 29.12, 30.53, 34.67, 44.24, 46.62, 51.11, 55.47, 63.80, 111.94,112.09, 116.78, 117.33, 117.48, 119.25, 131.23, 132.73, 136.98, 142.26,147.95, 148.56, 166.54, 168.06, 169.34, 171.70; Anal Calcd forC₃₀H₃₇N₃O₇+0.1 H₂O: C, 65.11; H, 6.78; N, 7.59. Found: C, 64.87; H,6.87; N, 7.48.

5.28. Example 28 (1S)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

To a solution of2-bromomethyl-6-(cyclopropanecarbonyl-amino)-3-fluoro-benzoic acidmethyl ester (1 g, 3 mmol) and Et₃N (1.25 ml, 9 mmol) in DMF (10 ml) wasadded (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine(870 mg, 3.2 mmol). The mixture was heated at 90° C. for 20 hrs. Thereaction mixture was cooled to room temperature and extracted with water(50 ml) and EtOAc (50 ml). The organic layer was washed with water (50ml), brine (25 ml), dried over Na₂SO₄ and concentrated. The resulted oilwas purified by chromatography to give (1S)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (800 mg, 55% yield): mp, 176–178° C.; ¹H NMR (CDCl₃) δ0.88–0.92 (m, 2H, c-propylCH₂), 1.09–1.12 (m, 2H, c-propylCH₂), 1.47 (t,J=7.0 Hz, 3H, OCH₂CH₃), 1.64–1.68 (m, 1H, c-propylCH), 2.98 (s, 3H,CH₃), 3.63–3.73 (m, 1H, CHHSO₂), 3.87 (s, 3H, CH₃), 4.05–4.28 (m, 4H,CHHSO₂+CNHH+OCH₂CH₃), 4.49 (d, J=18 Hz, 1H, CHHN), 6.85–6.92 (m, 1H,NCH), 6.86–6.93 (m, 3H, Ar), 7.04 (t, J=8 Hz, 1H, Ar), 8.45–8.55 (m, 1H,Ar), 10.32 (s, 1H, NHCO); ¹³C NMR (CDCl₃) δ 8.26, 8.27, 14.67, 16.04,41.50, 44.67, 51.30, 55.39, 55.96, 64.65, 111.63, 112.21, 118.95,119.26, 119.68, 119.92, 126.43, 126.74, 128.99, 134.48, 134.53, 148.98,149.88, 150.31, 154.22, 168.89, 172.39. Anal Calcd for C₂₄H₂₇FN₂O₆S: C,58.76; H, 5.55; N, 5.71. Found: C, 58.60; H, 5.33; N, 5.65.

5.29. Example 29(1S)-3-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea

To(1S)-7-amino-4-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one(800 mg, 1.82 mmol) was added dimethylcarbamyl chloride (3 ml). Themixture was heated at 100° C. for 20 hrs. The reaction mixture wascooled to room temperature and extracted with water (50 ml) and EtOAc(50 ml). The organic layer was washed with water (50 ml), brine (25 ml),dried over Na₂SO₄ and concentrated. The resulted oil was purified bychromatography to give(1S)-3-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea as a white solid (600 mg, 70% yield): mp, 205–207° C.;¹H NMR (CDCl₃) δ 1.47 (t, J=7.0 Hz, 3H, OCH₂CH₃), 2.94 (s, 3H, CH₃),3.11 (s, 6H, N(CH₃)₂), 3.72 (dd, J=5, 15 Hz, 1H, CHHSO₂), 3.88 (s, 3H,CH₃), 4.05–4.22 (m, 4H, CHHSO₂+CHHN+OCH₂CH₃), 4.40 (d, J=10 Hz, 1H,CHHN), 5.73–5.79 (m, 1H, NCH), 6.86–6.96 (m, 3H, Ar), 7.36 (d, J=9 Hz,1H, Ar), 8.35 (d, J=9 Hz, 1H, Ar), 9.77 (s, 1H, NHCO); ¹³C NMR (CDCl₃) δ14.68, 36.27, 41.51, 46.96, 51.47, 55.73, 55.97, 64.64, 111.64, 111.67,112.28, 118.20, 118.54, 119.31, 120.08, 129.13, 133.24, 138.58, 138.77,148.94, 149.88, 155.01, 169.72. Anal Calcd for C₂₃H₂₈ClN₃O₆S: C, 54.32;H, 5.65; N, 8.12. Found: C, 54.16; H, 5.42; N, 7.82.

5.30 Example 30(1S)-N-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-(4-methyl-piperazin-1-yl)-acetamide

To a solution of(1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide(250 mg, 0.48 mmol) in CH₃CN (10 ml) was added 1-methylpiperazine (0.21ml, 1.9 mmol). The mixture was heated at 70° C. for 2 hrs. The reactionmixture was concentrated on rota-vap and extracted with water (50 ml)and EtOAc (50 ml). The organic layer was washed with water (50 ml),brine (25 ml), dried over Na₂SO₄ and concentrated. The resulted oil waspurified by chromatography to give(1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-(4-methyl-piperazin-1-yl)-acetamideas a white solid (70 mg, 25% yield): mp, 205–207° C.; ¹H NMR (CDCl₃) δ1.47 (t, J=7.0 Hz, 3H, OCH₂CH₃), 2.36 (s, 3H, CH₃), 2.64 (broad, 8H, CH₂on piperazine ring), 2.99 (S, 3H, NCH₃), 3.21 (d, J=2 Hz, 2H, CH₂NCO),3.73 (dd, J=5, 15 Hz, 1H, CHHSO₂), 3.88 (s, 3H, OCH₃), 4.05–4.20 (m, 4H,CHHSO₂+CNHH+OCH₂CH₃), 4.39 (d, J=15 Hz, 1H, CHHN), 5.74–5.80 (m, 1H,NCH), 6.86–6.98 (m, 3H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.55 (d, J=8 Hz,1H, Ar), 11.45 (s, 1H, NHCO); ¹³C NMR (CDCl₃) δ 14.73, 41.37, 46.11,46.81, 51.57, 53.46, 54.81, 55.76, 55.98, 62.18, 64.62, 111.61, 112.42,119.46, 119.77, 119.87, 122.32, 129.20, 132.95, 135.98, 139.21, 148.93,149.87, 168.50, 170.01. Anal Calcd for C₂₇H₃₅ClN₄O₆S: C, 56.00; H, 6.09;N, 9.67. Found: C, 55.82; H, 5.79; N, 9.42.

5.31 Example 31(1S)-N-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-morpholin-4-yl-acetamide;Hydrochloride

To a solution of(1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide(250 mg, 0.48 mmol) in CH₃CN (10 ml) was added morpholine (0.17 ml, 1.94mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixturewas concentrated on rota-vap and extracted with water (50 ml) and EtOAc(50 ml). The organic layer was washed with water (50 ml), brine (25 ml),dried over Na₂SO₄ and concentrated. The resulted oil was purified bychromatography to give an oil which was stirred with HCl in ether (3 ml)to give(1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-morpholin-4-yl-acetamide;hydrochloride as a white solid (200 mg, 68% yield): mp, 198–200° C.; ¹HNMR (CDCl₃ with D₂O added) δ 1.46 (t, J=7.0 Hz, 3H, OCH₂CH₃), 2.68(broad, 4H, CH₂NCH₂ on morpholino ring), 2.99 (s, 3H, SCH₃), 3.24(broad, 2H, CH₂NCO), 3.72 (dd, J=5, 15 Hz, 1H, CHHSO₂), 3.87–3.92 (m,7H, OCH₃+CH₂OCH₂ on morpholine ring), 4.05–4.23 (m, 4H,CHHSO₂+CNHH+OCH₂CH₃), 4.40 (d, J=15 Hz, 1H, CHHN), 5.71–5.77 (m, 1H,NCH), 6.86–6.97 (m, 3H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.52 (d, J=8 Hz,1H, Ar); ¹³C NMR (CDCl₃) δ 14.75, 41.71, 47.09, 51.22, 51.59, 55.09,56.02, 63.81, 64.10, 64.81, 105.68, 111.67, 112.28, 119.32, 120.0,120.27, 124.03, 128.81, 133.20, 134.72, 139.41, 149.09, 150.01, 168.55.Anal Calcd for C₂₆H₃₃Cl₂N₃O₇S+0.53 H₂O: C, 51.02; H, 5.61; N, 6.87.Found: C, 50.70; H, 5.38; N, 6.76, 0.98% H₂O.

5.32 Example 32(1S)-N-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-dimethylamino-acetamide;Hydrochloride

To a solution of(1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide(400 mg, 0.78 mmol) in CH₃CN (10 ml) was added dimethylamine (2N inMeOH, 1.6 ml, 3.2 mmol). The mixture was heated at 70° C. for 2 hrs. Thereaction mixture was concentrated on rota-vap and extracted with water(50 ml) and EtOAc (50 ml). The organic layer was washed with water (50ml), brine (25 ml), dried over Na₂SO₄ and concentrated. The resulted oilwas purified by chromatography to give an oil which was stirred with HClin ether (3 ml) to give(1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-dimethylamino-acetamide;hydrochloride as a white solid (300 mg, 68% yield): mp, 198–200° C.; ¹HNMR (DMSO-d6) δ 1.32 (t, J=7.5 Hz, 3H, OCH₂CH₃), 2.87 (s, 6H, N(CH₃)₂),3.04 (s, 3H, CH₃), 3.74 (s, 3H, CH₃), 3.94–4.16 (m, 4H,OCH₂CH₃+NCHH+CHHSO₂), 4.36–4.50 (m, 3H, CHHSO₂+CH₂NCO), 4.73 (d, J=18Hz, 1H, CHHN), 5.85–5.91 (m, 1H, NCH), 6.98 (s, 2H, Ar), 7.05 (s, 1H,Ar), 7.69 (d, J=8 Hz, 1H, Ar), 8.18 (d, J=8 Hz, 1H, Ar), 10.21 (bs, 1H,HCl); 10.45 (s, 1H, NHCO); ¹³C NMR (DMSO-d6) δ 15.17, 23.25, 41.51,43.86, 46.03, 49.41, 53.88, 56.00, 58.52, 64.41, 112.50, 112.80, 120.23,121.25, 123.33, 130.22, 133.21, 134.72, 140.60, 148.55, 149.46, 154.53,167.02, 180.13. Anal Calcd for C₂₄H₃₁Cl₂N₃O₆S+0.41 H₂O: C, 50.78; H,5.65; N, 7.40. Found: C, 50.81; H, 5.55; N, 7.18; H₂O, 1.30.

5.33. Example 33 50 mg Solid Tablets

Tablets, each containing 50 mg of (1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,can be prepared in the following manner:

Constitutuents (for 1000 tablets) (1R)-Cyclopropanecarboxylicn acid{2-[2-carbamoyl- 50.0 g 1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide lactose 50.7 g wheat starch  7.5g polyethylene glycol 6000  5.0 g talc  5.0 g magnesium stearate  1.8 gdemineralized water q.s.

The solid ingredients are first forced through a sieve of 0.6 mm meshwidth. The active ingredient, lactose, talc, magnesium stearate and halfof the starch then are mixed. The other half of the starch is suspendedin 40 mL of water and this suspension is added to a boiling solution ofthe polyethylene glycol in 100 mL of water. The resulting paste is addedto the pulverulent substances and the mixture is granulated, ifnecessary with the addition of water. The granulate is dried overnightat 35° C., forced through a sieve of 1.2 mm mesh width and compressed toform tablets of approximately 6 mm diameter which are concave on bothsides.

5.34. Example 34 100 mg Solid Tablets

Tablets, each containing 100 mg of (1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,can be prepared in the following manner:

Constitutuents (for 1000 tablets) (1R)-Cyclopropanecarboxylicn acid{2-[2-carbamoyl- 100.0 g1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide . . . lactose 100.0 g wheatstarch  47.0 g magnesium stearate  3.0 g

All the solid ingredients are first forced through a sieve of 0.6 mmmesh width. The active ingredient, lactose, magnesium stearate and halfof the starch then are mixed. The other half of the starch is suspendedin 40 mL of water and this suspension is added to 100 mL of boilingwater. The resulting paste is added to the pulverised substances and themixture is granulated, if necessary with the addition of water. Thegranulate is dried overnight at 35° C., forced through a sieve of 1.2 mmmesh width and compressed to form tablets of approximately 6 mm diameterwhich are concave on both sides.

5.35. Example 35 75 mg Chewable Tablets

Tablets for chewing, each containing 75 mg of(1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,can be prepared in the following manner:

Composition (for 1000 tablets) (1R)-Cyclopropanecarboxylicn acid{2-[2-carbamoyl-  75.0 g1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide mannitol 230.0 g lactose 150.0 gtalc  21.0 g glycine  12.5 g stearic acid  10.0 g saccharin  1.5 g 5%gelatin solution q.s.

All the solid ingredients are first forced through a sieve of 0.25 mmmesh width. The mannitol are the lactose are mixed, granulated with theaddition of gelatin solution, forced through a sieve of 2 mm mesh width,dried at 50° C. and again forced through a sieve of 1.7 mm mesh width(1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,the glycine and the saccharin are carefully mixed, the mannitol, thelactose granulate, the stearic acid and the talc are added and the wholeis mixed thoroughly and compressed to form tablets of approximately 10mm diameter which are concave on both sides and have a breaking grooveon the upper side.

5.36. Example 36 10 mg Tablets

Tablets, each containing 10 mg (1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,can be prepared in the following manner.

Composition (for 1000 tablets) (1R)-Cyclopropanecarboxylicn acid{2-[2-carbamoyl-  10.0 g1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide lactose 328.5 g corn starch 17.5 g polyethylene glycol 6000  5.0 g talc  25.0 g magnesium stearate 4.0 g demineralized water q.s.

The solid ingredients are first forced through a sieve of 0.6 mm meshwidth. Then the active amide ingredient, lactose, talc, magnesiumstearate and half of the starch are intimately mixed. The other half ofthe starch is suspended in 65 mL and this suspension is added to aboiling solution of the polyethylene glycol in 260 mL of water. Theresulting paste is added to the pulverulent substances, and the whole ismixed and granulated, if necessary with the addition of water. Thegranulate is dried overnight at 35° C., forced through a sieve of 1.2 mmmesh width and compressed to form tablets of approximately 10 mmdiameter which are concave on both sides and have a breaking notch onthe upper side.

5.37. Example 37 100 mg Gelatin Capsules

Gelatin dry-filled capsules, each containing 100(1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,can be prepared in the following manner:

Composition (for 1000 tablets) (1R)-Cyclopropanecarboxylicn acid{2-[2-carbamoyl- 100.0 g1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide microcrystalline cellulose  30.0g sodium lauryl sulfate  2.0 g magnesium stearate  8.0 g

The sodium lauryl sulfate is sieved into (1R)-Cyclopropanecarboxylicacid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amidethrough a sieve of 0.2 mm mesh width and the two components areintimately mixed for 10 minutes. The microcrystalline cellulose is thenadded through a sieve of 0.9 mm mesh width and the whole is againintimately mixed for 10 minutes. Finally, the magnesium stearate isadded through a sieve of 0.8 mm width and, after mixing for a further 3minutes, the mixture is introduced in portions of 140 mg each into size0 (elongated) gelatin dry-fill capsules.

5.38. Example 27 Injectable Solution

A 0.2% injection or infusion solution can be prepared, for example, inthe following manner:

(1R)-Cyclopropanecarboxylicn acid {2-[2-carbamoyl- 5.0 g1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide sodium chloride 22.5 g phosphatebuffer pH 7.4 300.0 g demineralized water to 2500.0 mL

(1R)-Cyclopropanecarboxylic acid{2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideis dissolved in 1000 mL of water and filtered through a microfilter. Thebuffer solution is added and the whole is made up to 2500 mL with water.To prepare dosage unit forms, portions of 1.0 or 2.5 mL each areintroduced into glass ampoules (each containing respectively 2.0 or 5.0mg of amide).

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

1. A compound of formula (I):

wherein: Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—; X is H; Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH, (C₁₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), or CH₂NSO₂—(C₁₋₄-alkyl); R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or (C₁₋₄-alkyl)-cycloalkyl; R³ is, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl); R⁴ is H; R⁵ is —OH, or —O—C(O)R⁶; R⁶ is C₁₋₈-alkyl, amino-(C₁₋₈-alkyl), (C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl), C₃₋₆-cycloalkyl, phenyl, benzyl, or aryl; or a pharmaceutically acceptable salt, solvate, stereoisomer or clathrate thereof.
 2. The compound of claim 1, wherein Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH, (C₁₋₄-alkyl)-O(C₁₋₄-alkyl), (C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), or CH₂NSO₂(C₁₋₄-alkyl).
 3. The compound of claim 1 wherein R₁ is CH₃.
 4. The compound of claim 1 wherein R₂ is CH₂CH₃, CH₃, CH₂-cyclopropyl, or cyclopentyl.
 5. The compound of claim 1 wherein Y is —C(O)— or —CH₂—.
 6. An enantiomerically pure S isomer of a compound of claim 1, substantially free of its R isomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or clathrate thereof.
 7. An enantiomerically pure R isomer of a compound of claim 1, substantially free of its S isomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or clathrate thereof.
 8. A compound, wherein the compound is: (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino (tert-butoxy)formate; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-ureido-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[3-dimethylamino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide hydrochloride; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (3R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfinyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (3R)-3-[4-Chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid; (3R)-3-[4-Chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid methyl ester; (1R)-Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {7-chloro-2-[2-dimethylcarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1S)-Cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1S)-Cyclopropanecarboxylic acid {7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[2-cyclopropanecarbonyloxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-isobutyryloxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[2-(2,2-dimethyl-propionyloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-Cyclopropanecarboxylic acid {2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1S)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1S)-3-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea; or (1S)-N-{7-Chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-dimethylamino-acetamide hydrochloride.
 9. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof.
 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent and a compound of formula (I):

wherein: Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—; X is H; Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH, (C₁₋₄-alkyl)-O—(C₁₋₄-alkyl), (C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl), (C₀₋₄-alkyl)-SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)-NH₂, (C₀₋₄-alkyl)-N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), or CH₂NSO₂—(C₁₋₄-alkyl); R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or (C₁₋₄-alkyl)-cycloalkyl; R³ is, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl); R⁴ is H; R⁵ is —OH, or —O—C(O)R⁶; R⁶ is C₁₋₈-alkyl, amino-(C₁₋₈-alkyl), (C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl), C₃₋₆-cycloalkyl, phenyl, benzyl, or aryl; or a pharmaceutically acceptable salt or solvate thereof.
 11. The compound of claim 1, wherein said solvate is a hydrate.
 12. The enantiomerically pure S isomer of claim 6, wherein said solvate is a hydrate.
 13. The enantiomerically pure R isomer of claim 7, wherein said solvate is a hydrate. 